Defining risk-adapted adjuvant therapy in resectable pancreatic cancer: an editorial commentary on long-term outcomes from ESPAC4

Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related mortality in the USA and is expected to become the second by 2030 (1). Despite advancements in treatment, the 5-year median overall survival (OS) remains 13% across all stages (2). Surgery combined with chemotherapy offers the only potential for cure; however, only 16% of patients have resectable disease at diagnosis, and even in this select group, 5-year OS is approximately 44% (2). Survival outcomes have improved primarily due to advances in surgical techniques (3), and more importantly, multi-agent adjuvant chemotherapy regimens (4-13). Given that patients with early-stage disease have the greatest potential for cure, improving outcomes in this population remains crucial. However, defining the optimal management strategy is complex and continually evolving, particularly regarding the selection of adjuvant chemotherapy.

The role of adjuvant chemotherapy was first established through the landmark ESPAC1 (4,5) and CONKO-001 (6,7) trials, which demonstrated the survival benefits of chemotherapy with either 5-fluorouracil (5-FU) or gemcitabine, respectively, over observation alone. ESPAC3 later showed similar efficacy between 5-FU and gemcitabine, with gemcitabine preferred due to its lower toxicity profile (8). ESPAC4 built on this, demonstrating that the combination of capecitabine with gemcitabine (GemCap) improved OS vs. gemcitabine alone (9). Although the subsequent APACT trial (10,11) did not meet its primary endpoint of disease-free survival, longer follow-up revealed an OS benefit similar to GemCap, though the study was underpowered for this analysis. Further advances were made with the Unicancer PRODIGE-24/CCTG-PA6 trial, which demonstrated the superiority of mFOLFIRINOX (modified fluorouracil, leucovorin, irinotecan, and oxaliplatin) over gemcitabine (12) [for trial comparisons, refer to Tab. 1 in Palmer et al. (14)].

In this evolving landscape, Palmer et al. present “Pancreatic Adenocarcinoma: Long-Term Outcomes of Adjuvant Therapy in the ESPAC4 Phase III Trial”, which offers updated survival data after a median follow-up of 104 months (14). ESPAC4 was a phase III, open-label, multicenter randomized trial conducted at 92 hospitals across the United Kingdom, Germany, France, and Sweden (9). Patients aged ≥18 years who had undergone complete resection (R0 or R1) for PDA were randomized to receive either gemcitabine alone or GemCap within 12 weeks of surgery. The primary endpoint was OS in the intention-to-treat population. The initial analysis, which reported data after 458 deaths, showed a modest yet statistically significant OS benefit with GemCap, with a median OS of 28.0 months compared to 25.5 months for gemcitabine alone [hazard ratio (HR) 0.82, 95% confidence interval (CI): 0.68–0.98; P=0.03] (9).

In this updated long-term analysis, survival curves remained separated: median OS was 31.6 months for GemCap vs. 28.4 months for gemcitabine (HR 0.83, 95% CI: 0.71–0.98, P=0.03) and 5-year OS was 32% vs. 25%, respectively. The benefit was most pronounced in patients with lower post-operative disease burden. Among those with R0 resection, median survival was 49.9 months with GemCap compared to 32.2 months with gemcitabine (HR 0.63; 95% CI: 0.47–0.84; P=0.002). Similarly, lymph node-negative patients showed significantly higher 5-year OS rates with GemCap (59%) compared to gemcitabine alone (53%; HR 0.63; 95% CI: 0.41–0.98; P=0.04), a benefit not observed in patients with lymph node-positive disease (14).

Exploratory analyses based on PRODIGE-24/CCTG-PA6 eligibility criteria showed that approximately 26.4% of patients in ESPAC4 (193 of 732) would have been ineligible for mFOLFIRINOX, primarily due to elevated postoperative CA 19-9 levels (>180 kU/L) or starting adjuvant therapy outside the 12-week window (14). Among those eligible for PRODIGE-24/CCTG-PA6, there was a modest improvement in median OS (33.5 months with GemCap vs. 31.8 months with gemcitabine; P=0.07). However, for those ineligible for PRODIGE-24/CCTG-PA6, GemCap provided a clinically significant advantage, with median OS of 25.9 months compared to 20.7 months (HR 0.71, 95% CI: 0.52–0.98; P=0.04). Although the interaction test for eligibility by treatment effect was not significant (P=0.68), the trend supports GemCap as a preferred adjuvant therapy when mFOLFIRINOX is not feasible.

These long-term ESPAC4 data reinforce GemCap as a standard adjuvant therapy, providing sustained survival benefits over gemcitabine alone. This supports a tailored, risk-adapted approach to therapy: mFOLFIRINOX remains the preferred option for younger, fit patients with high-risk disease, while GemCap is a valuable alternative for patients with favorable postoperative features (R0 resection, node-negative) or for those unfit for intensive therapy, such as older adults. Although not directly compared to mFOLFIRINOX, the broader eligibility criteria of ESPAC4 enhance its applicability to real-world practice.

These results, however, come at a time when adjuvant therapy decisions are evolving in parallel with the growing use of neoadjuvant and perioperative chemotherapy for resectable PDA. Large retrospective studies increasingly support neoadjuvant therapy for resectable PDA, citing improved survival and disease control compared to upfront surgery. For example, a National Cancer Database (NCDB) study of over 5,000 patients with clinical T1–T2 resectable PDA showed that multi-agent neoadjuvant chemotherapy (NAC) was associated with a median OS of 35.8 months compared to 27.1 months with upfront surgery (15). After adjusting for contributing clinical factors, multi-agent therapy reduced the risk of death by 23% compared to upfront surgery, with benefits consistent across demographic and clinical characteristics (15).

Similarly, a Surveillance, Epidemiology, and End Results (SEER) program analysis of 13,674 patients with stage I–III PDA found that NAC, with or without chemoradiation, significantly improved OS compared to upfront surgery for stage IB–III disease (16). No survival benefit was observed for stage IA tumors, indicating that tumor burden likely influences the effectiveness of neoadjuvant therapy. These results were consistent with multivariable Cox regression models, reinforcing that neoadjuvant therapy is particularly beneficial for patients with locally advanced but still resectable disease (16).

Smaller institutional series have reported even greater benefits. One propensity-matched cohort of 202 patients found that NAC or chemoradiation led to significantly longer progression-free survival (PFS) (29.6 vs. 13.2 months, P<0.001) and OS (72.7 vs. 28.3 months, P=0.03) compared with upfront surgery, along with higher R0 resection rates (74.3% vs. 49.5%) and lower rates of lymphovascular invasion (20.0% vs. 52.4%) (17). Similarly, a single-center study found that patients receiving total neoadjuvant therapy (TNT) or NAC had longer OS and recurrence-free survival (RFS) compared with those who underwent upfront surgery (18). Of those treated with TNT, 88.5% underwent surgical resection, compared to 82.1% in the NAC group. The mean RFS for TNT, NAC, and surgery-first groups were 17.5, 25.7, and 16.3 months, respectively (P<0.01). At 1 year, survival rates were 96.0%, 88.7%, and 66.3%, and at 3 years, 65.6%, 49.2%, and 28.0%, respectively (18).

Prospective trials are now beginning to confirm these benefits. The PANACHE01-PRODIGE48 trial (19), a multicenter, randomized phase II study, assigned patients with resectable PDA to receive four cycles of either neoadjuvant mFOLFIRINOX, four cycles of FOLFOX (folinic acid, fluorouracil, and oxaliplatin), or upfront surgery. The primary endpoints included 1-year OS and post-randomization therapy completion rate. In the intention-to-treat analysis, 70.8% of patients completed mFOLFIRINOX (90% CI: 60.8–79.6) and 68% completed FOLFOX (90% CI: 55.5–78.8). The FOLFOX arm was discontinued after the first interim analysis due to lack of efficacy. The mFOLFIRINOX arm showed improved event-free survival (EFS) of 51.4% (95% CI: 41.0–64.3), compared to 38.7% (95% CI: 24.1–62.0) in the upfront surgery group (19).

These findings suggest that neoadjuvant therapy can improve treatment completion rates, enhance pathological outcomes, and prolong survival compared to upfront surgery for many patients with resectable PDA. Increasingly, patients who would have previously been treated postoperatively in trials like ESPAC4 are now receiving systemic therapy up front, reflecting the recognition of pancreatic cancer’s systemic nature, the value of assessing treatment response before surgery, and the risk of postoperative delays in initiating adjuvant therapy.

It is important to recognize the benefits of neoadjuvant or perioperative therapy are not universal. For patients with clearly upfront resectable, low-risk disease, the advantages may be limited. Several randomized trials have failed to show a clear benefit in this setting. NORPACT-1 (20), the largest randomized trial in resectable pancreatic head cancer, compared neoadjuvant FOLFIRINOX with upfront surgery but failed to demonstrate an OS benefit with systemic therapy; in fact, survival was numerically longer in the surgery-first arm. NEPAFOX (21) evaluated a perioperative FOLFIRINOX approach against upfront surgery followed by adjuvant gemcitabine; the trial was stopped early for poor accrual and ultimately did not show a survival advantage with NAC. Similarly, SWOG S1505 (22) compared perioperative mFOLFIRINOX and gemcitabine/nab-paclitaxel in resectable PDA, but neither arm achieved superior survival outcomes compared to historical benchmarks. Similarly, meta-analyses restricted to strictly resectable PDA populations conclude that neoadjuvant strategies do not consistently improve outcomes over upfront resection (23,24). These findings underscore that while neoadjuvant therapy can optimize systemic treatment delivery and improve surgical outcomes, it may not provide added value for low-risk resectable PDA and should therefore be applied selectively.

As these practices continue to evolve, other strategies, such as intensifying neoadjuvant or perioperative treatment, are being explored. For example, the phase III CASSANDRA trial (13) compared perioperative PAXG (cisplatin, nab-paclitaxel, capecitabine, gemcitabine) with mFOLFIRINOX in patients aged 75 years or younger with resectable or borderline resectable PDA. Treatment was delivered either entirely preoperatively or split between preoperative and postoperative phases. The primary analysis demonstrated that PAXG significantly improved 3-year EFS compared to mFOLFIRINOX (30% vs. 14%; HR 0.66, 95% CI: 0.49–0.89; P=0.005), with higher disease control rates (98% vs. 91%), greater CA 19-9 reduction, and higher rates of pathologic stage less than II (13). Resection rates were similar between arms, with neutropenia more frequent in the PAXG group (13).

The ongoing Alliance A021806 phase III trial (NCT04340141) (25) is expected to provide further clarity on whether perioperative therapy should replace adjuvant-only strategies in resectable disease. In this trial, patients with resectable PDA and good performance status are randomized to receive either 8 cycles of neoadjuvant mFOLFIRINOX followed by 4 cycles postoperatively, or upfront surgery followed by 12 cycles of adjuvant mFOLFIRINOX. This study aims to establish the optimal sequencing of systemic therapy and surgery in resectable PDA (25).

An expanding understanding of the molecular landscape of PDA is increasingly poised to further impact treatment decisions across all stages of the disease, including resectable disease. The identification of distinct transcriptional subtypes, such as the classical and basal-like subtypes, has already begun to shape therapeutic strategies. The classical subtype, associated with a more favorable prognosis, contrasts with the basal-like subtype, which tends to exhibit worse prognosis and reduced sensitivity to mFOLFIRINOX across multiple retrospective cohorts (26). Efforts are underway to better understand how to incorporate these transcriptional subtypes into treatment paradigms.

Emerging data from prospective studies further support the association between PDA subtype and clinical outcomes. In the COMPASS trial (27), patients with untreated, unresectable or metastatic PDA underwent whole genome and RNA sequencing prior to their first-line chemotherapy regimen. Those with classical tumors exhibited higher objective response rates and numerically longer PFS, indicating that these tumors may be more amenable to standard treatments. Conversely, basal-like tumors experienced shorter survival and poorer responses to mFOLFIRINOX, suggesting the need for alternative therapeutic strategies in this population (27). Early results from PASS-01 (28), a randomized trial comparing gemcitabine/nab-paclitaxel with mFOLFIRINOX in de novo metastatic PDA, revealed comparable outcomes for classical tumors with both regimens. However, basal-like tumors showed diminished benefit from mFOLFIRINOX, further supporting results from the previous COMPASS trial.

Recently, results from the prospective NeoPancONE (29) phase II study have expanded on these findings by assessing the efficacy of perioperative mFOLFIRINOX in patients with centrally confirmed resectable PDA, when patients are stratified by transcriptional subtyping performed on baseline endoscopic fine-needle biopsies. This trial demonstrated that basal-like tumors had significantly worse outcomes, with a 1-year OS rate of 75% compared to 87% for classical tumors. Furthermore, basal-like tumors had higher rates of progression within six months (42% vs. 12%, P=0.02) (29). These results suggest that neoadjuvant mFOLFIRINOX may not be the optimal approach for patients with basal-like PDA, highlighting the growing importance of upfront molecular subtyping to guide treatment selection and improve patient outcomes.

Alongside transcriptional subtyping, genomic profiling is increasingly influencing treatment decisions in PDA. One of the most actionable genomic alterations is homologous recombination deficiency, commonly driven by pathogenic mutations in BRCA1, BRCA2, or PALB2. In the metastatic setting, the phase III POLO trial established the use of maintenance olaparib for patients with germline BRCA1 or BRCA2 mutations who had not progressed after at least 16 weeks of platinum-based chemotherapy, demonstrating a significant improvement in PFS (30). A subsequent phase II study of rucaparib extended this benefit to patients with either germline or somatic mutations in BRCA1, BRCA2, or PALB2. Of the 46 patients enrolled, 27 had germline BRCA2 mutations, 7 had germline BRCA1 mutations, 6 had germline PALB2 mutations, and 2 had somatic BRCA2 mutations. The median PFS was 13.1 months, with a median OS of 23.5 months, and notable efficacy was observed in patients with germline PALB2 and somatic BRCA2 mutations (31).

Building on this evidence, the ongoing APOLLO trial (EA2192) is evaluating 1 year of adjuvant olaparib vs. placebo following curative-intent treatment to include surgical resection and at least 4 months of chemotherapy around surgery, with or without chemoradiation, in patients with germline or somatic BRCA1, BRCA2, or PALB2-mutated PDA (32). This trial aims to determine whether the benefits of PARP inhibition observed in the advanced/metastatic setting can be translated into earlier-stage disease, potentially reshaping the role of targeted therapy in the adjuvant treatment paradigm for this select population.

Looking ahead, the rapid development of novel RAS inhibitors offers another promising avenue for molecularly targeted therapy in resectable PDA, particularly given the near-universal prevalence of KRAS mutations. Early-phase data have shown encouraging antitumor activity, and ongoing trials such as RASolute-302 (33), which is evaluating a tricomplex pan-RAS inhibitor vs. standard of care chemotherapy in the second-line setting, are assessing efficacy in metastatic disease. As these agents progress, a key question will be how to integrate them into the adjuvant paradigm. The trajectory of RAS inhibitors may follow a path similar to other cancers, like non-small cell lung cancer (NSCLC), where targeted therapies initially demonstrated efficacy in advanced disease before being introduced into the adjuvant setting. For example, adjuvant osimertinib has improved disease-free survival in resected EGFR-mutated NSCLC, with or without prior adjuvant chemotherapy (34), and adjuvant alectinib has reduced recurrence risk in completely resected ALK-positive disease (35). A similar molecularly driven strategy in PDA, informed by comprehensive genetic profiling, could enable more precise selection of adjuvant therapies and lead to improved long-term outcomes for patients.

Ultimately, treatment selection in resected PDA must balance efficacy, tolerability, and patient-specific factors. The mature data from the ESPAC4 trial reinforce GemCap’s role for patients who are ineligible for mFOLFIRINOX or those with favorable postoperative features. However, as treatment strategies evolve toward neoadjuvant or perioperative approaches and biomarker-driven therapies, the future of PDA management will likely focus on integrating tumor biology into treatment sequencing. This personalized approach could significantly improve survival outcomes for patients with resectable PDA, highlighting the importance of tailored therapy based on individual molecular profiles.

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-25-25/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-25-25/coif). E.S.N. receives grants from Black Diamond Therapeutics, EXoPERT, Pfizer, and Revolution Medicines. A.L.C receives grants from Actuate Therapeutics, Amgen, BeiGene, Boundless Bio, Kyowa Kirin, Mirati Therapeutics, Novocure, Pfizer, PMV, Novartis. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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