Combining PARP and PD-1 inhibition in a patient with esophagogastric adenocarcinoma (EGA)

Introduction Esophagogastric adenocarcinoma (EGA) is one of the leading causes of cancer- related mortality worldwide. Therapeutic options are limited for patients with recurrent or metastatic disease. Targeted therapy may be a suitable treatment for selected patients, but its efficacy remains elusive. Case Presentation Here, a 52-year-old male patient with advanced EGA Siewert Type II shows a significant response to combination therapy with olaparib and pembrolizumab. After progression following first- and second-line therapy, including a programmed cell death ligand 1 (PD-L1) inhibitor, next-generation sequencing of a tumor sample was performed to identify possible molecular targets. A mutation in RAD51C, a member of the Homology-directed repair (HDR) system, was identified in addition to high PD-L1 expression. As a result, therapy with the Poly-(ARD-Ribose) Polymerase (PARP) inhibitor olaparib and the Programmed cell death protein 1 (PD1)-inhibitor pembrolizumab was initiated. A durable partial response lasting for more than 17 months was observed. A second molecular profiling from a newly occurring subcutaneous metastasis showed a loss of FGF10 but no fluctuations in the gene alteration of RAD51C and SMARCA4. Interestingly, the new lesion showed HER2-positivity (Immunohistochemistry (IHC) 3+ and Fluorescence in situ hybridisation (FISH)-positivity) in 30% of tumor cells. Discussion/Conclusion In this case, a long-lasting response to the combination of olaparib and pembrolizumab was observed despite previous treatment with a PD-L1 inhibitor. This case illustrates the need for further clinical trials to analyze the efficacy of PARP inhibitor combinations in EGA.