# Systemic Therapy for Metastatic Pancreatic Cancer

## TL;DR

This paper reviews treatment options for metastatic pancreatic cancer, emphasizing chemotherapy, targeted therapies like PARP inhibitors, and the potential of personalized approaches.

## Contribution

The paper highlights the role of BRCA1/2 testing and emerging strategies like tumor-organoid-informed treatment in metastatic pancreatic cancer.

## Key findings

- PARP inhibitors like olaparib improve progression-free survival in BRCA1/2-mutated metastatic pancreatic cancer patients.
- Second-line treatment with 5-FU/FA plus nanoliposomal irinotecan improves overall survival compared to 5-FU/FA alone.
- Immune checkpoint inhibitors benefit only a small subset of metastatic pancreatic cancer patients with high microsatellite instability.

## Abstract

Pancreatic cancer is mainly diagnosed at an advanced, often metastatic stage and still has a poor prognosis. Over the last decades, chemotherapy of metastatic pancreatic cancer (mPDAC) has proven to be superior to a mere supportive treatment with respect to both survival and quality of life. Recently, even sequential treatment of mPDAC could be established. Options for first-line treatment are combination chemotherapy regimens such as FOLFIRINOX and gemcitabine plus nab-paclitaxel when the performance status of the patient is good. For patients with poorer performance status, gemcitabine single-agent treatment is a valid option. Recently, the PARP inhibitor olaparib has been demonstrated to improve progression-free survival when used as a maintenance treatment in the subgroup of patients with mPDAC and a BRCA1/-2 germ line mutation having received at least 16 weeks of platinum-based chemotherapy. This group of patients also benefits from platinum-based chemotherapy combinations. Therefore, the BRCA1/-2 stats should be examined early in patients with mPDAC even when the occurrence of these mutations is only about 5% in the general Caucasian population. After the failure of first-line treatment, patients should be offered a second-line treatment if their ECOG permits further treatment. Here, the combination of 5-FU/FA plus nanoliposomal irinotecan has shown to be superior to 5-FU/FA alone with respect to overall survival. Immune checkpoint inhibitors like PD1/PD-L1 mAbs are particularly efficacious in tumors with high microsatellite instability (MSI-h). Limited data in mPDACs shows that only a part of the already small subgroup of MSI-H mPDACs (frequency about 1%) appears to benefit substantially from a checkpoint inhibitor treatment. The identification of further subgroups, e.g., tumors with DNA damage repair deficiency, gene fusions, as well as novel approaches such as tumor-organoid-informed treatment decisions, may further improve therapeutic efficacy.