Pancreatic adenocarcinoma is a lethal condition, which has currently become the third leading cause of cancer-related deaths in the United States (National Cancer Institute, 2025). Despite advancements in chemotherapy, the overall prognosis for patients with metastatic pancreatic adenocarcinoma remains unfavorable due to its diverse molecular subgroups and unique biological characteristics (Von Hoff et al., 2013; Conroy et al., 2011; Park et al., 2021; Wainberg et al., 2023). Hence, understanding the molecular basis of different genomic mutation profiles is critical for implementing biomarker-directed therapy.

BRCA1 and BRCA2 are crucial proteins involved in homologous recombination repair (HRR), loss of function of these genes results in homologous recombination deficiency (HRD) (Tutt and Ashworth, 2002). Approximately 4%–7% of pancreatic adenocarcinoma harbor germline BRCA mutations (gBRCAm) (Holter et al., 2015). This genetic characteristic confers enhanced sensitivity to platinum-based agents and poly (adenosine diphosphate–ribose) polymerase (PARP) inhibitors in pancreatic adenocarcinoma patients (Ghiorzo, 2014; O'Reilly et al., 2020; Kindler et al., 2022). The landmark POLO trial established that olaparib represents the standard maintenance therapy in patients with metastatic pancreatic adenocarcinoma harboring gBRCAm who demonstrated sensitivity to platinum-based chemotherapy (Golan et al., 2019).

Fuzuloparib is a novel, potent, and orally bioavailable PARP inhibitor that has demonstrated superior in vivo efficacy and improved safety profile compared to olaparib in preclinical studies (Li et al., 2020a). In the FZOCUS-2 study, fuzuloparib as maintenance therapy achieved statistically significant survival improvement with tolerable adverse events in patients with platinum-sensitive recurrent ovarian cancer (Li et al., 2022). However, clinical data regarding fuzuloparib as maintenance therapy in pancreatic adenocarcinoma remains limited.

Here, we present a remarkable case of a patient with extensively metastatic pancreatic adenocarcinoma harboring gBRCAm, who demonstrated sensitive to NALIRIFOX chemotherapy. Notably, the tumor lesions exhibited continued modest regression during subsequent maintenance fuzuloparib.

A 33-year-old asymptomatic Asian woman was found to have masses in pancreatic tail and liver on routine screening, with ECOG performance status 0. Positron emission tomography-computed tomography (PET-CT) (1 March 2024), revealed a solid-cystic mass in the pancreatic tail and multiple hypermetabolic hepatic lesions (Figure 1; Supplementary Figure A1). Serum CA19-9 level was elevated at 186 U/mL (normal range: <37 U/mL) (Figure 2). Liver biopsy confirmed pancreatic adenocarcinoma with the following immunohistochemical (IHC) markers: CK7 (+), CK8/18 (+), CD56 (−), CK5/6 (−), CR (−), WT1 (−), p63 (−), CDX2 (−), CK20 (−), HepPar-1 (−), and Ki-67 (20%). Comprehensive next-generation sequencing (NGS) analysis revealed a pathogenic germline BRCA2 nonsense mutation (Table 1). Notably, the patient reported no relevant personal history of cancer or family history of BRCA-associated malignancies.

Given the gBRCAm, first-line treatment with NALIRIFOX was initiated on 17 April 2024 (Figure 1). After four cycles, CT showed a deep and rapid partial response (PR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), with CA19-9 dropping to 56.4 U/mL (Figure 2). The impressive response continued with ongoing treatment. (Figures 1, 2).

After 12 cycles of NALIRIFOX induction therapy, the patient achieved significant treatment response with CA19-9 reduction from 174 to 31.2 U/mL and sustained PR confirmed by CT imaging per RECIST v1.1 (Figure 2). Given the stable disease with continued tumor shrinkage, excellent performance status (ECOG 0), patient preference for oral maintenance therapy, and cumulative oxaliplatin-induced peripheral neuropathy following multiple cycles of platinum-based chemotherapy, maintenance therapy with fuzuloparib 150 mg twice daily was initiated in November 2024, resulting in continued PR and CA19-9 normalization to 11.5 U/mL (Figures 1, 2). This dose of fuzuloparib was selected based on existing clinical trial data demonstrating optimal efficacy and tolerability profiles (Li et al., 2020a; Li et al., 2022; Wei et al., 2024). However, severe hematologic toxicities developed in March 2025, including grade 4 anemia (hemoglobin 49 g/L; normal range: 110–150 g/L), grade 3 leukopenia (white blood cell 2.91 × 10⁹/L; normal range: 4.0–10.0 × 10⁹/L), grade 3 thrombocytopenia (platelets 83 × 10⁹/L; normal range: 100–300 × 10⁹/L), and grade 3 neutropenia (neutrophils 1.5 × 10⁹/L; normal range: 2.0–7.0 × 10⁹/L) according to Common Terminology Criteria for Adverse Events (CTCAE v5.0) criteria. Following supportive care including blood transfusion and granulocyte colony-stimulating factor (G-CSF) administration, along with fuzuloparib dose reduction to 100 mg twice daily, the patient continues on maintenance therapy with resolved toxicities (Figure 1), demonstrating grade 1 anemia (hemoglobin 99 g/L) with normalized white blood cell and platelet counts. Notably, following fuzuloparib dose reduction, the pancreatic and hepatic lesions exhibited further modest regression, and serum CA19-9 levels continued to decline (Figure 2). As of 21 June 2025, the patient has achieved progression-free survival (PFS) exceeding 15 months, with ongoing fuzuloparib maintenance therapy for over 7 months.

We present a remarkable case of a female patient with metastatic pancreatic adenocarcinoma harboring gBRCAm. Following 12 cycles of NALIRIFOX induction therapy, she achieved PR. Continued modest tumor regression was observed during subsequent fuzuloparib maintenance therapy.

GBRCAm provides unique therapeutic opportunities for pancreatic adenocarcinoma (Golan et al., 2014). Platinum-based chemotherapies exert their cytotoxic effect by binding directly to DNA, causing crosslinking of DNA strands and inducing DNA double-strand breaks, which cannot be effectively repaired in pancreatic adenocarcinoma with pathogenic or likely pathogenic gBRCA mutations (Farmer et al., 2005; Li et al., 2020b). This phenomenon results in preferential tumor cell death and confers superior survival outcomes to patients with gBRCA variants treated with platinum-based chemotherapy, which was validated in many clinical trials (O'Reilly et al., 2020; Golan et al., 2014; Wattenberg et al., 2020). In our case, considering the patient’s germline BRCA2 nonsense mutation, we prioritized NALIRIFOX or FOLFIRINOX as first-line therapy. Based on the favorable survival outcomes demonstrated by NALIRIFOX in the NAPOLI-3 study, NALIRIFOX was ultimately selected (Wainberg et al., 2023). Moreover, the patient demonstrated excellent tumor regression and survival following 12 cycles of NALIRIFOX induction chemotherapy, which underscores the important role of biomarker-directed therapy in first-line chemotherapy selection for pancreatic cancer.

PARP inhibitors represent a targeted therapeutic approach for pancreatic adenocarcinoma with gBRCAm. PARP inhibitors exploit homologous recombination deficiency by inhibiting base excision repair and trapping PARP enzymes, ultimately leading to replication fork collapse and inducing lethal double-strand DNA breaks specifically in BRCA-deficient tumors (Das et al., 2024). Although the POLO study demonstrated survival benefits of olaparib as maintenance therapy in pancreatic cancer patients harboring gBRCAm, olaparib also exhibited significant hematological and gastrointestinal toxicities (Golan et al., 2019). Fuzuloparib, as a novel PARP inhibitor, demonstrated superior in vivo efficacy and reduced toxicity compared to olaparib in preclinical studies and clinical studies (Li et al., 2020a; Topatana et al., 2020). However, clinical data for fuzuloparib in gastrointestinal malignancies remains limited. Currently, only a phase Ib study conducted in 2023 explored the efficacy of fuzuloparib combined with chemotherapy in pancreatic cancer, demonstrating that fuzuloparib maintenance therapy following FOLFIRINOX in advanced pancreatic adenocarcinoma showed favorable efficacy and manageable tolerability (Wei et al., 2024). Additional studies have reported that fuzuloparib 150 mg twice daily as maintenance therapy demonstrated favorable efficacy and tolerability profiles in lung and ovarian cancers (Li et al., 2022; Li et al., 2023). In this case, considering the patient’s economic constraints, we selected maintenance fuzuloparib as maintenance therapy in this case. Although the patient developed grade 4 myelosuppression after 2 months of fuzuloparib 150 mg twice daily, sustained modest tumor regression with tolerant adverse events was observed following dose reduction. These findings suggest that fuzuloparib may represent a potential PARP inhibitor option for maintenance treatment in pancreatic adenocarcinoma with gBRCAm; however, large-scale randomized controlled trials are needed to validate these results.

With the emergence of targeted therapies for KRAS mutations, DNA damage repair deficiencies, and mismatch repair pathways, targeted treatment has become a research hotspot in pancreatic cancer (Li et al., 2024). In this case, the patient harbored additional mutations in TSC2, FLT4, and TGFBR2 genes. Research on targeted therapies for FLT4 and TGFBR2 mutations remains limited in pancreatic cancer. TSC2 functions as a key negative regulator of mTORC1 signaling (Manning and Cantley, 2003). However, the efficacy of mTOR inhibitors such as everolimus and ridaforolimus in pancreatic cancer remains controversial (Mortazavi et al., 2022). Some studies have demonstrated that in TSC2-mutated cancer both combination therapy with PD-1 and CTLA-4 antibodies, as well as monotherapy, can enhance CD8⁺ T cell infiltration in TSC2-deficient human tumors, with the level of infiltration correlating with treatment response (Liu et al., 2018). In 2021, a case report documented successful clinical outcomes using this approach in pancreatic cancer (Wang et al., 2014). However, further clinical research is currently lacking to support this perspective. These genetic alterations may provide potential avenues for future targeted and immunotherapy strategies in pancreatic cancer patients.

This study presents a remarkable case of gBRCAm metastatic pancreatic adenocarcinoma that demonstrated a durable response to fuzuloparib after NALIRIFOX chemotherapy. This case further reinforces the important role of biomarker-directed therapy in pancreatic adenocarcinoma. Furthermore, it underscores that fuzuloparib may represent a potential PARP inhibitor option for maintenance treatment in pancreatic adenocarcinoma with gBRCAm; however, large-scale randomized controlled trials are needed to validate these results.