Review
PARP inhibitors alone and in combination with other biological agents in homologous recombination deficient epithelial ovarian cancer: From the basic research to the clinic

https://doi.org/10.1016/j.critrevonc.2017.04.006Get rights and content

Abstract

Hereditary epithelial ovarian cancer [EOC] in germline BRCA mutation (gBRCAm) carriers has a distinct clinical behavior characterized by younger age, high- grade serous histology, advanced stage, visceral distribution of disease, high response to platinum and other non-platinum agents and better clinical outcome. Sporadic EOC with homologous recombination deficiency [HDR] but no gBRCAm has the same biological and clinical behavior as EOC in gBRCAm carriers (“BRCAness”phenotype). Biomarkers are in development to enable an accurate definition of molecular features of BRCAness phenotype, and trials are warranted to determine whether such HDR signature will predict sensitivity to PARP inhibitors in sporadic EOC. Moreover, the link between PARP inhibition and angiogenesis suppression, the immunologic properties of EOC in gBRCAm carriers, the HRD induced by PI3K inhibition in EOC cells in vitro strongly support novel clinical trials testing the combination of PARP inhibitors with other biological agents.

Introduction

Epithelial ovarian cancer [EOC] is the sixth most common malignancy among women worldwide and causes more deaths per year than any other cancer of the lower genital tract (Siegel et al., 2014). The standard treatment of early disease consists of surgery with a comprehensive staging procedure, followed by adjuvant carboplatin [CBDCA] or paclitaxel [PTX]-CBDCA based-chemotherapy in high-risk cases (Collinson et al., 2014, Trimbos, 2016). Cytoreductive surgery followed by PTX-CBDCA based chemotherapy is the mainstay of care for advanced EOC, whereas neoadjuvant chemotherapy followed by interval debulking surgery is indicated for women with high perioperative risk profile or with low likelihood of achieving an optimal cytoreduction to <1 cm residual disease [RD] and ideally to non visible RD (Wright et al., 2016).

Approximately 13–31% of patients with early EOC and 75–80% of those with advanced EOC and no clinical evidence of disease after primary treatment relapse after a median interval of 11–29 months and 18–24 months, respectively (Gadducci et al., 2009).

Patients with recurrent EOC receive second-line chemotherapy, mainly dependent on platinum-free interval and persistent toxicities. Single agents, such as weekly PTX, peghylated lyposomal doxorubicin [PLD] and gemcitabine [GEM], are given to patients with platinum-resistant or refractory disease (Pujade-Lauraine et al., 2014). CBDCA doublets, i.e. CBDCA in combination with PTX, GEM or PLD, are used in patients with platinum-sensitive disease (Parmar et al., 2003, Pfisterer et al., 2006, Pujade-Lauraine et al., 2010) and the combination of PLD + trabectedin is an interesting therapeutic option for those who have partially platinum-sensitive disease as well as for those who have fully-platinum sensitive disease but who are not fit for platinum rechallenge (Poveda et al., 2014).

However the unsatisfactory results obtained with salvage chemotherapy have elicited investigators to detect novel biological agents able to achieve a better control of disease (Rodriguez-Freixinos et al., 2016). Two types of molecular targeted therapies, i.e anti-angiogenic agents and poly(adenosine diphosphate[ATP-ribose] polymerases [PARP] inhibitors, have been shown to be active in randomized clinical trials and have been approved by regulatory agencies. The addition of bevacizumab, a humanized monoclonal antibody [mAb] against all major forms of Vascular Endothelial Growth Factor [VEGF], to standard chemotherapy has obtained a significant improvement in progression-free survival [PFS] but not in overall survival [OS] in the first-line treatment of advanced EOC (Burger et al., 2011, Perren et al., 2011) as well as in the second-line treatment of both recurrent platinum-sensitive disease (Aghajanian et al., 2012) and recurrent platinum-resistant disease (Pujade-Lauraine et al., 2014). The emergence of the DNA repair pathways as a rational target in cancer therapy has led to the development of the PARP inhibitors that have obtained very promising results in EOC (Ledermann, 2016). The present review analyses the literature data on the clinical relevance of DNA repair defects, on the activity of PARP inhibitors and on the combination of PARP inhibitors with other biological agents in the management of EOC.

Section snippets

DNA repair mechanisms and BRCA status

DNA single strand breaks [SSB]s, resulting from endogenous and exogenous genotoxic agents, are repaired by nucleotide excision repair [NER], by mismatch repair [MMR] and predominantly by base excision repair [BER] (Bernstein et al., 2002, Abbotts, 2016). PARPs are nuclear proteins that sense and bind to SSBs and, after a structural change, activate the BER pathway by recruiting other DNA-repairing enzymes including DNA ligase III, DNA polymerase-β and scaffolding proteins such as X-ray

Potential biomarkers of homologous recombination deficiency other than BRCA mutation

Sporadic EOCs with HR deficiency [HDR] but no BRCA1-2 mutations have the same histological pattern, biological characteristics and clinical behavior as hereditary EOC with gBRCAm (“BRCAness”phenotype) (Turner et al., 2004, Murata et al., 2016).

Ataxia-telangiectasia, mutated [ATM] is serine/threonine kinase specifically activated in response to DSBs, that plays a major role in phosphorylating a network of proteins involved in controlling cell cycle checkpoints and DNA repair (Lee, 2007). The

Mechanisms of action and resistance

Tumors with compromised ability to repair DSBs because of HRD, are highly sensitive to blockade of the repair of SSBs via PARP inhibition (Saleh-Gohari et al., 2005, Ashworth, 2008, Meehan and Chen, 2016). The development of PARP inhibitors has provided the basis for a novel synthetic lethal therapeutic approach, where two deficiencies each having no effect on the cellular outcome become lethal when combined together.

In addition to catalytic inhibition of SSB repair, PARP inhibitors themselves

Antiangiogenic agents

There is a link between PARP inhibition and suppression of angiogenesis (Pyriochou et al., 2008, Rodríguez et al., 2013, Tentori et al., 2007). Chronic hypoxia induces down-regulation of BRCA1 and RAD51 and decreases HR in cancer cells, whereas it does not impair NHEJ pathway (Chan et al., 2008, Neumeister et al., 2012, Bindra et al., 2005, Bindra et al., 2004, Chan et al., 2010). The definition “contextual’ synthetic lethality” has been suggested for therapeutic approach to induce HRD by

Conclusions

Olaparib has obtained the greatest clinical benefit as maintenance treatment in patients with platinum-sensitive, recurrent EOC with gBRCAm or tumor BRCA mutation. Moreover, durable responses to single-agent olaparib have also been reported in patients with recurrent gBRCAm EOC who had received ≥3 lines of prior chemotherapy. European Medicines Agency [EMA] has approved olaparib as maintenance treatment of patients with platinum-sensitive, recurrent germline or somatic BRCA-mutated HGSOC who

A. Gadducci obtained his residency in Gynecology and Obstetrics, Oncology and Nuclear Medicine. He is a full professor in Gynecologic and Obstetric, Department of Clinical and Experimental Medicine, University of Pisa. Chief of the committee for guidelines in diagnosis and treatment of gynecologic tumors of the Tuscan Tumor Institute.

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