Exceptional synergistic response of PARP inhibitor and immune checkpoint inhibitor in esophageal adenocarcinoma with a germline BRCA2 mutation: a case report

Abstract

Immune checkpoint inhibitors (ICIs) and poly (ADP-ribose) polymerase (PARP) inhibitors have shown efficacy in various tumors. A significant therapeutic challenge with either ICIs or PARP inhibitors as monotherapy is treatment failure from intrinsic primary resistance or the development of secondarily acquired resistance after a period of responsiveness. The combination of PARP inhibitors and ICIs could mitigate this by potentiating treatment response. We describe an 83-year-old male patient who initially presented with abdominal pain, and weight loss along with alternating constipation and diarrhea. Imaging and biopsy revealed metastatic esophageal adenocarcinoma. Genomic testing revealed germline BRCA2 mutation. The patient initially underwent a few cycles of chemoimmunotherapy. However, due to intolerance to chemotherapy, the patient's case was discussed at a multidisciplinary molecular tumor board. He was switched to PARP inhibitor olaparib and ICI nivolumab. This combination led to a durable complete response. A combination of poly-ADP ribose polymerase inhibitor (PARPi) plus ICI may work in synergy through various mechanisms including enhanced neoantigen expression, release of immune-activating cytokines, and increased programmed death-ligand 1 expression. This may culminate in accentuated efficacy outcomes with a manageable safety profile. This exceptional response with ICI and PARPi in our case is consistent with the synergistic value of this combination, and prospective studies are warranted to definitively characterize clinical utility.

Keywords: BRCA; DNA repair; PARP; combination therapy; esophageal cancer; homologous recombination; immune checkpoint inhibitor.

Figure 1.

PET scans at diagnosis and 4 months after PARP inhibitor and ICI therapy. (a) Axial fused images from PET/CT prior to treatment show hypermetabolic primary mass at GEJ (left), hypermetabolic metastatic upper abdominal lymphadenopathy, and right hepatic lesion (right). (b) Axial fused images from PET/CT after eight cycles of treatment with nivolumab and olaparib show complete resolution of the primary GEJ mass (left) as well as the metastatic upper abdominal lymphadenopathy and right hepatic lesion (right). CT, computed tomography; GEJ, gastroesophageal junction; ICI, immune checkpoint inhibitor; PARP, poly (ADP-ribose) polymerase; PET, positron emission tomography.

Figure 2.

Timeline of events. The figure shows the timeline of events from diagnosis to last follow-up. ctDNA, circulating tumor DNA; FOLFOX, 5-fluorouracil plus oxaliplatin; MRD, minimal residual disease; NGS, next-generation sequencing.

Figure 3.

Prevalence of germline BRCA2 mutation (a) compared to the total number of cases in a particular type of cancer (b) compared to the total number of cases with germline BRCA2 mutations. CM, cutaneous melanoma; EC, esophageal carcinoma; IBC, invasive breast carcinoma; OV, ovarian carcinoma; PAC, pancreatic adenocarcinoma; PRAD, prostate adenocarcinoma.