Quantitative Analysis of the Efficacy of PARP Inhibitors as Maintenance Therapy in Recurrent Ovarian Cancer.

Lili Gao,Lujin Li,Ting Li,Rui Chen,Qingshan Zheng

doi:10.3389/fphar.2021.771836

Abstract

Objective: This study aimed to establish a pharmacodynamic model and to screen reasonable covariates to quantitatively describe the efficacy of poly (ADP-ribose) polymerase inhibitors (PARPis) as maintenance treatment for recurrent ovarian cancer (ROC). Methods: The log normal hazard function model was established by using progression-free survival (PFS) data of 1,169 patients from published randomized trials on FDA-approved PARP inhibitors (olaparib, niraparib, and rucaparib). Monte Carlo simulation was used to compare PFS values in different scenarios, such as monotherapy (administered alone) and combination therapy (PARPis combined with chemo- or target-therapies), different biomarker statuses, and different PARP inhibitors. PFS was also estimated. Results: The study showed that the median PFS was 8.5 months with monotherapy and 16.0 months with combination therapy. The median PFS of patients with the BRCA mutation, BRCA wild-type, and HRD-positivity were 11.0, 7.5, and 9.0 months in monotherapy, respectively, and 23.0, 14.0 and 17.5 months, in combination therapy, respectively. In addition, the median PFS of olaparib, niraparib, and rucaparib monotherapy were about 9.5, 10.5, and 12.0 months, respectively, and about 19.0, 20.0, and 25 months, respectively, in combination therapy. The median PFS values in combination with cediranib, bevacizumab, and chemotherapy were approximately 17.0, 12.5 and 19.5 months, respectively. Conclusion: PARPi combination therapy is more effective as maintenance treatment for ROC than monotherapy, and the efficacy of PARPis in combination with chemotherapy is higher than that of the combination with antiangiogenic drugs. We found that the PFS of BRCA wild-type was similar to that of HRD-positive patients, and there was no significant difference in PFS between olaparib, niraparib, and rucaparib, which provides necessary quantitative information for the clinical practice of PARPis in the treatment of ROC.

Highlights

Ovarian cancer is a malignant gynecological tumor with a high mortality rate
669 patients tested positive for breast-related cancer antigens (BRCA) mutations (BRCAm) and a 100 patients tested positive for wild-type BRCA (BRCAwt). 400 patients were homologous recombination deficiency (HRD)-positive
The combined drugs included antiangiogenic drugs: 21 patients and 43 patients for bevacizumab and cediranib, respectively, and 28 patients received a PARPi combined with a chemotherapy drug

Summary

Introduction

Ovarian cancer is a malignant gynecological tumor with a high mortality rate. It is traditionally treated with cytoreductive surgery and chemotherapy, but the recurrence rate in patients is high (Ma et al, 2020). (ADP-ribose) polymerase (PARP) inhibitors (PARPis) have ushered in a new era for the treatment of ovarian cancer. PARPis kill tumor cells by blocking single-strand DNA break repair and through PARP “trapping” in tumor cells that lack the ability to repair double-strand DNA damage, such as breast-related cancer antigens (BRCA) mutations and/or homologous recombination deficiency (HRD) (Kotsopoulos et al, 2016). As of August 2020, the FDA had approved three PARPis for the maintenance treatment of recurrent ovarian cancer (ROC): olaparib (Food and Drug Administrat, 2020a), rucaparib (Food and Drug Administrat, 2020b), and niraparib (Food and Drug Administrat, 2020c).

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Discussion

Conclusion