ReviewPARP inhibitors alone and in combination with other biological agents in homologous recombination deficient epithelial ovarian cancer: From the basic research to the clinic
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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2021, Cancer Treatment ReviewsCitation Excerpt :Therefore, in theory, the triple targeting of angiogenic, DNA damage response, and immune checkpoint pathways can enhance the antitumor effects of each mode of treatment and confer resistance escape mechanisms to one another Many reviews describing clinical trials examining the use of PARPi monotherapy or PARPi plus immunotherapy combinations (Table 3) in ovarian cancer have already been published [80,85–87] and will not be discussed here. Our understanding of PARP inhibition and antiangiogenic combinations has also progressed significantly over the past few years, and key clinical trials are summarized in Table 2.
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2021, PathologyCitation Excerpt :More specifically, current hypothesis indicates that PARP inhibitors are effective only in case of loss of function or biallelic inactivation of HRD related genes (i.e., germline mutation plus somatic loss, or double-somatic alterations).51 Impressive responses to the PARP inhibitor olaparib were observed in patients with advanced ovarian and breast carcinomas harbouring germline mutations in BRCA1 and BRCA2 genes.52,53 In addition, some BRCA-wildtype ovarian carcinomas equally seem susceptible to PARP inhibitors,54 emphasising the need for biomarkers of HRD signature (‘BRCAness’ phenotype).
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2019, Gynecologic OncologyCitation Excerpt :More recently, however, PARPi approval was expanded to maintenance therapy for patients with platinum-sensitive relapsed ovarian cancer, who responded to their second line regimen, regardless of BRCA1 or BRCA2 (BRCA1/2) mutation status [27,28]. This broader use of PARPi stems from the evidence that tumors that share molecular features with BRCA-mutant tumors (i.e., BRCAness) also exhibit different levels of defective homologous recombination DNA repair, and therefore will respond to PARP inhibition [29]. Importantly however, recent results from large prospective randomized clinical trials have demonstrated significant PARPi clinical activity also against patients harboring HR-competent/BRCA wild-type tumors [30].
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.
M.E. Guerrieri obtained her degree in Medicine and Surgery.