Revisiting neoadjuvant strategies in pancreatic cancer: insights from CASSANDRA

Pancreatic ductal adenocarcinoma (PDAC) remains as one of the most lethal cancers worldwide. Surgical resection is the cornerstone for curative treatment, however only roughly 10% of patients present with upfront resectable disease. In these patients, the management approach has traditionally been upfront resection followed by adjuvant therapy, typically consisting of mFOLFIRINOX or gemcitabine-based regimens (1,2).

In recent years, neoadjuvant strategies have gained traction for several reasons. First, recurrence rates after upfront surgery remain high, even among patients with negative margins and node-negative disease. Moving systemic therapy earlier into the neoadjuvant space allows for prompt treatment of occult metastatic disease. Second, a substantial proportion of patients who undergo upfront surgery are not able to complete adjuvant therapy due to postoperative morbidity or functional decline. Third, neoadjuvant therapy allows for a test of tumor biology where patients with rapid disease progression despite systemic treatment can potentially be spared from futile surgery.

Neoadjuvant approaches typically involve chemoradiation or combination systemic therapy, however the optimal approach remains unclear. Chemoradiation was evaluated in the PREOPANC trial that demonstrated an improvement in 5-year overall survival (20.5% vs. 6.5%) with neoadjuvant gemcitabine-based chemoradiation versus upfront surgery in patients with resectable and borderline resectable PDAC, with a modest improvement in median overall survival (1.4 months). In this trial, the adjuvant therapy in both groups consisted of single-agent gemcitabine, which limits its applicability to current practice (3).

As for neoadjuvant systemic therapy approaches, gemcitabine and S-1 was compared to upfront surgery in a phase II/III trial (Prep-02/JSAP05) among patients with resectable PDAC with both arms pursuing adjuvant S-1. The study found an improvement in overall survival with neoadjuvant therapy (37.0 vs. 26.6 months), with no significant reduction in resection rates (4). On the other hand, the phase II NORPACT-1 trial failed to demonstrate a survival benefit with neoadjuvant FOLFIRINOX compared to upfront surgery in patients with resectable PDAC, despite an improvement in R0 resection rates. This study was limited by high rates of non-completion of the planned neoadjuvant treatment (5). ALLIANCE A021806 (NCT04340141) and PREOPANC-3 (NCT04927780) are two ongoing phase III trials comparing six months of perioperative mFOLFIRINOX against six months of adjuvant mFOLFIRINOX in resectable PDAC, and will help clarify the optimal timing of systemic therapy using current standard regimens (6,7).

Few studies have directly compared neoadjuvant strategies in resectable/borderline resectable PDAC. Gemcitabine-based chemoradiation was evaluated against FOLFIRINOX in the phase III PREOPANC-2 trial, and both were found to have similar outcomes in overall survival, progression-free survival, R0 resection rates and pathologic complete response. This suggests that both neoadjuvant approaches may be considered in these patients (8).

CASSANDRA (PACT-21), published in The Lancet in December 2025, is notable for directly comparing two combination systemic therapy regimens in the neoadjuvant setting for resectable and borderline resectable PDAC. It is a randomized open-label study conducted across 17 Italian academic centers, enrolling 260 patients (9). Originally designed as a phase II trial, it was later re-classified to phase III after results of PREOPANC-2 were published. The study was built on prior phase II data from the same group that showed favorable progression-free survival with cisplatin, nab-paclitaxel, capecitabine and gemcitabine (PAXG) compared to gemcitabine plus nab-paclitaxel in the metastatic setting (10).

The study employed a 2×2 factorial design with a first randomization to four months of either neoadjuvant mFOLFIRINOX or PAXG. Patients then underwent a second randomization to either immediate surgery followed by two months of adjuvant chemotherapy, or two additional months of preoperative chemotherapy followed by surgery (9). The primary endpoint was event-free survival (EFS) which was defined as a composite of (1) radiological progression, (2) disease recurrence, (3) two consecutive carbohydrate antigen 19-9 (CA19-9) increases of at least 20% and at least 4 weeks apart, (4) unresectability, (5) intraoperative metastasis, and (6) death.

Results from the first randomization have been reported with a median follow-up of 28.5 months, and showed a significant improvement in median EFS with PAXG compared to mFOLFIRINOX (16.0 vs. 10.2 months, P=0.0018). Subgroup analyses suggested a greater EFS advantage for PAXG among patients with resectable disease (19.1 vs. 10.4 months) relative to those with borderline resectable disease (12.4 vs. 10.2 months). In addition, disease control rate, CA19-9 response, early pathological stage, node positivity, and intraoperative or early postoperative metastases also favored the PAXG group. Grade 3 or worse adverse events were similar between the two arms (66% vs. 61%), while grade 3–4 neutropenia was more frequent with PAXG (43% vs. 29%) (9).

Several aspects of the trial design warrant caution in interpreting these findings. The lack of a data and safety monitoring board, and absence of central pathology and radiology review are limitations of this trial. There were also minor imbalances between the two groups with a higher proportion of patients with stage I disease (54% vs. 45%) and germline BRCA1/2 variants (11% vs. 4%) in favor of the PAXG arm.

Of note, the definition of EFS used in the study incorporated CA19-9 rise, and the use of this novel composite endpoint has not yet been validated in pancreatic cancer. Events based on CA19-9 rise alone (18% of total events) were numerically more frequent with mFOLFIRINOX compared with PAXG (21 vs. 12 events), and it was unclear how patients with this event were subsequently managed in the trial (9). Sensitivity analysis based on the standard EFS definition would be helpful to evaluate the robustness of the study findings.

Furthermore, patients in the PAXG group were more likely to have completed neoadjuvant therapy (76% vs. 67%) and had a longer median duration of treatment (162 vs. 132 days), which may have also contributed to differences in outcomes between the two arms (9). It would be helpful to expound on reasons for early chemotherapy discontinuation in order to clarify whether these were due to toxicity, CA19-9 rise alone, or true disease progression. If there was early treatment discontinuation solely due to CA19-9 rise, this would raise concerns regarding a potential impact on long-term outcomes.

Overall survival data remain essential to interpret these results in a potentially curative patient population. Although upfront use of four active agents may improve early disease control, it may also limit the availability of effective therapies at recurrence in a disease where relapse is common. Consequently, gains in event-free survival may not necessarily translate into overall survival benefit if treatment sequencing is compromised, underscoring the importance of overall survival in this context.

Taken together, CASSANDRA provides evidence that PAXG may improve disease control when used in the neoadjuvant setting for PDAC. However, whether this translates to a meaningful survival advantage remains uncertain, given the absence of mature overall survival data. While EFS is an appealing early endpoint, it has not been definitively validated as a surrogate for cure in PDAC, and thus should be interpreted with caution. As such, longer-term data are needed before PAXG could be considered a standard neoadjuvant regimen for PDAC. Importantly, CASSANDRA does not address the question of whether neoadjuvant therapy improves outcomes compared to upfront surgery in resectable disease, which remains the focus of ongoing trials such as ALLIANCE A021806 and PREOPANC-3.

From a broader perspective, there is increasing recognition that PDAC is a genetically and biologically heterogenous disease whereby certain features can influence its aggressiveness and response to treatment. For example, molecular subtyping allows for the identification of a basal-like phenotype that is associated with resistance to standard systemic therapy options and worse survival (11). This phenotype, predicted by low GATA6 expression, has been associated with early disease progression in resectable PDAC treated with neoadjuvant mFOLFIRINOX (12). Incorporating phenotype assessment on future studies can provide insights on the potential for tailored treatment approaches. In addition, emerging therapies such as KRAS inhibitors have demonstrated encouraging activity in advanced disease, and may in the future have a role in the perioperative setting (13). Studies prospectively investigating adaptive approaches based on response to neoadjuvant therapy are also worth pursuing (14).

At present, CASSANDRA adds to the growing body of evidence for neoadjuvant therapy in resectable and borderline resectable PDAC, however the optimal approach remains unclear. Results from ongoing phase III trials, including ALLIANCE A021806 and PREOPANC-3, together with advances in biomarker-driven approaches, will be crucial to define the best strategy in this setting.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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