University of Oulu

Boussios, S.; Karihtala, P.; Moschetta, M.; Karathanasi, A.; Sadauskaite, A.; Rassy, E.; Pavlidis, N. Combined Strategies with Poly (ADP-Ribose) Polymerase (PARP) Inhibitors for the Treatment of Ovarian Cancer: A Literature Review. Diagnostics 2019, 9, 87.

Combined strategies with poly (ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer : a literature review

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Author: Boussios, Stergios1,2; Karihtala, Peeter3; Moschetta, Michele4;
Organizations: 1Acute Oncology Assessment Unit, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, Kent, UK
2AELIA Organization, 9th Km Thessaloniki-Thermi, 57001 Thessaloniki, Greece
3Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, P.O. Box 22, 90029 Oulu, Finland
4Drug Development Unit, Sarah Cannon Research Institute, 93 Harley Street, London W1G 6AD, UK
5Department of Pharmacy, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, Kent, UK
6Department of Cancer Medicine, Gustave Roussy Institut, 94805 Villejuif, France
7Department of Hematology-Oncology, Hotel Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University, 166830 Beirut, Lebanon
8Medical School, University of Ioannina, Stavros Niarchou Avenue, 45110 Ioannina, Greece
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.3 MB)
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Language: English
Published: Multidisciplinary Digital Publishing Institute, 2019
Publish Date: 2020-04-21


Poly (ADP-ribose) polymerase (PARP) inhibitors are the first clinically approved drugs designed to exploit synthetic lethality, and were first introduced as a cancer-targeting strategy in 2005. They have led to a major change in the treatment of advanced ovarian cancer, and altered the natural history of a disease with extreme genetic complexity and defective DNA repair via homologous recombination (HR) pathway. Furthermore, additional mechanisms apart from breast related cancer antigens 1 and 2 (BRCA1/2) mutations can also result in HR pathway alterations and consequently lead to a clinical benefit from PARP inhibitors. Novel combinations of PARP inhibitors with other anticancer therapies are challenging, and better understanding of PARP biology, DNA repair mechanisms, and PARP inhibitor mechanisms of action is crucial. It seems that PARP inhibitor and biologic agent combinations appear well tolerated and clinically effective in both BRCA-mutated and wild-type cancers. They target differing aberrant and exploitable pathways in ovarian cancer, and may induce greater DNA damage and HR deficiency. The input of immunotherapy in ovarian cancer is based on the observation that immunosuppressive microenvironments can affect tumour growth, metastasis, and even treatment resistance. Several biologic agents have been studied in combination with PARP inhibitors, including inhibitors of vascular endothelial growth factor (VEGF; bevacizumab, cediranib), and PD-1 or PD-L1 (durvalumab, pembrolizumab, nivolumab), anti-CTLA4 monoclonal antibodies (tremelimumab), mTOR-(vistusertib), AKT-(capivasertib), and PI3K inhibitors (buparlisib, alpelisib), as well as MEK 1/2, and WEE1 inhibitors (selumetinib and adavosertib, respectively). Olaparib and veliparib have also been combined with chemotherapy with the rationale of disrupting base excision repair via PARP inhibition. Olaparib has been investigated with carboplatin and paclitaxel, whereas veliparib has been tested additionally in combination with temozolomide vs. pegylated liposomal doxorubicin, as well as with oral cyclophosphamide, and topoisomerase inhibitors. However, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations requires further investigation with dose escalation studies. In this review, we discuss multiple clinical trials that are underway examining the antitumor activity of such combination strategies.

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Series: Diagnostics
ISSN: 2075-4418
ISSN-E: 2075-4418
ISSN-L: 2075-4418
Volume: 9
Issue: 3
Article number: 87
DOI: 10.3390/diagnostics9030087
Type of Publication: A2 Review article in a scientific journal
Field of Science: 3122 Cancers
Copyright information: © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (