Combinatorial Therapy of High Dose Vitamin C and PARP Inhibitors in DNA Repair Deficiency: A Series of 8 Patients

Abstract

Background: Tumor-specific DNA repair defects are ubiquitous in cancerous tissue, which offers a potential for clinical gain to build on these perturbations. Intravenous high-dose vitamin C (IVC) triggers the formation of hydrogen peroxide (H 2 O 2 ), which contributes to Fenton chemistry producing hydroxyl radicals (-OH), causing selective damage to DNA. Herein, we evaluated the therapeutic response to IVC and PARP inhibitors (PARPi) in combination in 8 patients with a deficiency of homologous recombination repair system (dHRR) in a 3-year period. Material and Methods: Eight patients with progressive stage IV malignancy, who were pre-treated with conventional methods, were admitted to our clinic. Subsequent therapy has included IVC at a dose that was set to be in the range of 1 to 1.5 g/kg, although 1.25 g/kg was dominantly administered. Furthermore, following genomic evaluation, PARPi (niraparib or olaparib or talazoparib) was chosen to be used in combination with IVC which was administered 2 to 4 times a week. Results: In the present study, we achieved partial response in 5 patients and complete response in 3 patients. Grade 2 anemia and fatigue toxicities were observed in some cases, while grade 3 toxicity was not found in any of the patients. Conclusion: Our 8 patient case study shows that IVC could be a plausible additional therapy for HRR deficiency. Although the single agent PARPi therapy is effective for metastatic disease, an overall survival (OS) advantage has not been demonstrated. Our results suggest that adding IVC can improve PARPi therapy outcomes. To fully endorse the results stated above, combinatorial therapy of intravenous high dose vitamin C and PARP inhibitors needs to be reviewed in broader cohorts of patients.