Poly (ADP-ribose) Polymerase Inhibitors In Ovarian Cancer Research Articles

Abstract 7135: Preclinical effects of Tumor Treating Fields (TTFields) with PARP inhibitors in ovarian cancer

Abstract Purpose: Among gynecological malignancies, ovarian cancer is the leading cause of mortality. Poly (ADP-ribose) polymerase inhibitors (PARPi) represent standard-of-care treatment for selected cases of advanced epithelial ovarian cancer. PARPi exhibit sensitivity in homologues recombination deficient (HRD) tumors, in which there are mutations in the Fanconi Anemia (FA)-BRCA pathway, while about 75% of ovarian cancer patients are homologues recombination proficient (HRP). TTFields are non-invasive electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression. Recent research showed that TTFields induce an HRD-like state (also known as BRCAness state) in various cancer types. The current study aims to investigate the impact of TTFields applied together with PARPi in ovarian cancer preclinical models. Methods: In vitro, A2780 (HRP), OVCAR3 (HRD), and A2780cis (platinum-resistant) ovarian cancer cells were treated with TTFields (1 V/cm RMS, 200 kHz, 72 h), alone or with addition of PARPi (olaparib or niraparib, at various concentrations). Efficacy was measured by analyzing cell count, colony formation, and apoptosis induction. The overall effect was calculated by multiplying cell count with colony formation. TTFields-treated cells were evaluated for the expression of FA-BRCA pathway proteins and for formation of γH2AX, a DNA damage marker, using Western blot and fluorescent microscopy, respectively. In vivo, ID8-fLuc (HRP) cells were inoculated intraperitoneally to 6-8-week-old C57BL/6 mice. Seven days post inoculation, mice were treated with sham-vehicle, TTFields, olaparib (50 mg/kg), or both over a period of four weeks. Tumor growth was analyzed using bioluminescent imaging at treatment cessation, and survival analysis was performed. Results: TTFields application resulted in reduced cell count, increased overall effect, and increased apoptosis in vitro. When TTFields were applied together with PARPi, a high and moderate synergistic interaction was shown respectively the BRCA wild-type A2780 cells and the platinum-resistant A2780cis cells. However, in the BRCA mutant OVCAR-3 cells the effect was additive. A downregulation of FA-BRCA protein expression was confirmed after TTFields treatment of the ovarian cells, with consequent DNA damage. In the tumor-bearing mice, TTFields and olaparib co-treatment resulted in reduced tumor volume and a survival benefit relative to the monotherapies and to control-treated mice. Conclusions: The data suggest potential advantages for TTFields concomitant with PARPi in ovarian cancer, even without underlying BRCA mutations - consistent with the BRCAness state induced by TTFields - and also suggests benefits in platinum-resistant ovarian cancer. Citation Format: Yani Berckmans, Hila Ene, Kerem Ben-Meir, Antonia Martinez-Conde, Roni Monin, Bieke Van den Ende, Sara Van Mechelen, Roni Frechtel-Gerzi, Hila Gabay, Rotem Engelman, Eyal Dor-On, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti, Ignace Vergote, An Coosemans. Preclinical effects of Tumor Treating Fields (TTFields) with PARP inhibitors in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7135.

PARP Inhibitors in Ovarian Cancer: A Review.

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have transformed the ovarian cancer (OC) treatment landscape. This narrative review provides a comprehensive overview of data for the PARPis olaparib, niraparib, and rucaparib in patients with OC and discusses their role in disease management, with a focus on the use of PARPis as maintenance therapy in the United States (US). Olaparib was the first PARPi to be approved as first-line maintenance monotherapy in the US, with maintenance niraparib subsequently approved in the first-line setting. Data also support the efficacy of rucaparib as first-line maintenance monotherapy. PARPi maintenance combination therapy (olaparib plus bevacizumab) also provides benefit in patients with newly diagnosed advanced OC whose tumors tested positive for homologous recombination deficiency (HRD). Biomarker testing is critical in the newly diagnosed setting to identify patients most likely to benefit from PARPi maintenance therapy and guide treatment decisions. Clinical trial data support the use of PARPis (olaparib, niraparib, rucaparib) as second-line or later maintenance therapy in patients with platinum-sensitive relapsed OC. Although distinct differences in tolerability profile were observed between PARPis, they were generally well tolerated, with the majority of adverse events managed by dose modification. PARPis had no detrimental effect on patients' health-related quality of life. Real-world data support the use of PARPis in OC, although some differences between PARPis are apparent. Data from trials investigating novel combination strategies, such as PARPis plus immune checkpoint inhibitors, are awaited with interest; the optimal sequencing of novel therapies in OC remains to be established.

Abstract 2669: RRM2 inhibition synergizes with PARP inhibitor in ovarian cancer cells

Abstract The use of Poly(ADP-ribose) polymerase inhibitors (PARPi) has been applied for the treatment of epithelial ovarian cancer (EOC) patients with homologous recombination (HR)-deficient disease, such as BRCA1/2 mutations. However, 40 - 70% of patients do not initially respond to PARPi in ovarian cancer with non-BRCA mutations, and acquired resistance has been demonstrated clinically. Ribonucleotide reductase (RNR, which consists of two RRM1 subunits and two RRM2 subunits) is the rate-limiting enzyme in the biosynthesis of dNTPs for DNA replication and DNA damage repair. As targeting RRM2 has been applied for many cancer therapies clinically or in clinical trials, this study hypothesizes that the inhibitory of RRM2 arguments PARPi potency against ovarian cancer. To this goal, this study evaluates the therapeutic effects of RRM2 inhibitor Osalmid (a resveratrol analog) alone or combined with PARPi by employing a panel of ovarian cancer cell lines using SRB assay. The effects on apoptosis and cell-cycle arrest were analyzed using flow cytometry. The cellular thermal shift assay was conducted to explore if Osalmid interacts with RRM2. DNA double strand break marker, ϒH2AX, was detected in compound-treated cells using Western blot. The results provide a new synthetic lethality by combining RRM2 inhibitor and PARPi. The combination induced apoptosis and caused the cell-cycle arrest. The results show that Osalmid binds to RRM2 directly. This study provides both a novel RRM2 inhibitor from a natural compound and a new understanding of the dNTP metabolic demands and may lead to urgently-needed strategies for the treatment of ovarian cancer. Citation Format: Chi-Wei Chen. RRM2 inhibition synergizes with PARP inhibitor in ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2669.

Clinical Landscape of PARP Inhibitors in Ovarian Cancer: Molecular Mechanisms and Clues to Overcome Resistance.

Simple SummaryRecent development of maintenance therapy using PARP inhibitors in ovarian cancer has led to a significant improvement in survival rates. However, resistance to these inhibitors can occur in patients, causing disease progression or relapse. Consequently, novel treatment strategies are urgently needed to overcome this resistance. This review article focuses on the precise molecular mechanisms by which PARP inhibitors exert their antitumor effects, as well as how they elicit resistance, in order to gain insight into novel therapeutic approaches to overcome PARP inhibitor resistance in ovarian cancer.The survival of patients with advanced or recurrent ovarian cancer has improved tremendously in the past decade, mainly due to the establishment of maintenance therapy with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) after conservative chemotherapies. Despite their superior efficacy, resistance to PARPis has been reported, and patients with resistance have a much worse prognosis. Therefore, the development of novel treatment strategies to overcome PARPi resistance is urgently needed. The present review article focuses on the molecular mechanisms of how PARPis exert cytotoxic effects on cancer cells through DNA repair processes, especially the genetic background and tumor microenvironment favored by PARPis. Furthermore, currently available information on PARPi resistance mechanisms is introduced and discussed to develop a novel therapeutic approach against them.

Research progress on the association between environmental pollutants and the resistance mechanism of PARP inhibitors in ovarian cancer.

The occurrence and progression of ovarian cancer are closely related to genetics and environmental pollutants. Poly(ADP-ribose) polymerase (PARP) inhibitors have been a major breakthrough in the history of ovarian cancer treatment. PARP is an enzyme responsible for post-translational modification of proteins and repair of single-stranded DNA damage. PARP inhibitors can selectively inhibit PARP function, resulting in a synthetic lethal effect on tumor cells defective in homologous recombination repair. However, with large-scale application, drug resistance also inevitably appears. For PARP inhibitors, the diversity and complexity of drug resistance mechanisms have always been difficult problems in clinical treatment. Herein, we mainly summarized the research progress of DNA damage repair and drug resistance mechanisms related to PARP inhibitors and the impact of environmental pollutants on DNA damage repair to aid the development prospects and highlight urgent problems to be solved.

PARP inhibitors in ovarian cancer: evidence for maintenance and treatment strategies.

Ovarian cancer is the most lethal gynecologic malignancy. The long-established primary treatment for ovarian cancer consisted of surgical cytoreduction followed by platinum-based chemotherapy. Unfortunately, this therapeutic approach is related to a high frequency of early relapses. Further chemotherapy is necessary for recurrent disease, but very few patients can be cured. Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in various DNA repair activities. PARP inhibition leads to synthetic lethality in BRCA mutated or homologous recombination deficient tumors. The development of PARP inhibitors has changed the way ovarian cancer patients are treated. Olaparib, niraparib and rucaparib are orally active and have demonstrated efficacy for both maintenance and treatment settings. These three drugs have gained regulatory approval for different clinical circumstances. They have an acceptable toxicity profile and are generally well tolerated. Common class toxicities include hematologic effects, gastrointestinal effects and fatigue. Moreover, new treatment strategies that combine PARP inhibitors with other drugs, such as angiogenic agents, are being explored. The purpose of this review is to describe the evidence that define the current clinical role of PARP inhibitors in ovarian cancer. The implementation of rationally designed new clinical trials will be crucial to facilitate the best selection of patients and to continue improving clinical outcomes.

Use of First-Line PARP Inhibitors in Ovarian Cancer

Platinum-based chemotherapy regimens are the mainstay of advanced ovarian cancer treatment. However, up to 85% of the patients experience recurrence under these settings. To fill this gap, novel front-line treatment strategies have been established, leading to unprecedented clinical benefits. For example, first-line bevacizumab, an anti-angiogenic agent, plus chemotherapy followed by bevacizumab maintenance, has emerged as a new standard of care for newly diagnosed high risk ovarian cancer patients. This was based on the results of the phase III GOG 0218 and ICON-7 trials. More recently, poly(ADP)-ribose polymerase (PARP) inhibitors, including niraparib, olaparib and veliparib, have offered a new treatment option as part of the front-line treatment in ovarian cancer. Here we provide an overview of three recent studies that may lead to a paradigm shift in the first-line treatment for advanced ovarian cancer.

PARP Inhibitors in Ovarian Cancer: The Route to "Ithaca".

Poly (ADP-ribose) polymerase (PARP) inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Genomic instability characterizes high-grade serous ovarian cancer (HGSOC), with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Early studies have shown significant efficacy for PARP inhibitors in patients with germline breast related cancer antigens 1 and 2 (BRCA1/2) mutations. It has also become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this treatment. Companion homologous recombination deficiency (HRD) scores are being developed to guide the selection of patients that are most likely to benefit from PARP inhibition. The choice of which PARP inhibitor is mainly based upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of patients most likely to benefit from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The aim of this review is to describe the current evidence for PARP inhibitors in ovarian cancer, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolution of resistance.

PARP inhibitors in ovarian cancer: Sensitivity prediction and resistance mechanisms.

Poly (ADP‐ribose) polymerase (PARP) inhibitors have provided great clinical benefits to ovarian cancer patients. To date, three PARP inhibitors, namely, olaparib, rucaparib and niraparib have been approved for the treatment of ovarian cancer in the United States. Homologous recombination deficiency (HRD) and platinum sensitivity are prospective biomarkers for predicting the response to PARP inhibitors in ovarian cancers. Preclinical data have focused on identifying the gene aberrations that might generate HRD and induce sensitivity to PARP inhibitors in vitro in cancer cell lines or in vivo in patient‐derived xenografts. Clinical trials have focused on genomic scar analysis to identify biomarkers for predicting the response to PARP inhibitors. Additionally, researchers have aimed to investigate mechanisms of resistance to PARP inhibitors and strategies to overcome this resistance. Combining PARP inhibitors with HR pathway inhibitors to extend the utility of PARP inhibitors to BRCA‐proficient tumours is increasingly foreseeable. Identifying the population of patients with the greatest potential benefit from PARP inhibitor therapy and the circumstances under which patients are no longer suited for PARP inhibitor therapy are important. Further studies are required in order to propose better strategies for overcoming resistance to PARP inhibitor therapy in ovarian cancers.

Olaparib as maintenance treatment for patients with platinum-sensitive relapsed ovarian cancer.

Poly (ADP-ribose) polymerase (PARP) inhibitors were developed with the intention of treating patients with homologous recombination repair deficiency (HRD), specifically for patients with tumours that harbour a BRCA mutation (BRCAm). Evidence from clinical trials to date has demonstrated that patients with a BRCAm derive the greatest benefit from PARP inhibitors. However, clinical studies have also shown that PARP inhibitors provide benefit to women with ovarian cancer who do not have a BRCAm. The recent updated approvals of olaparib, niraparib and rucaparib by the US Food and Drug Administration and the European Medicines Agency for the treatment of all platinum-sensitive relapsed (PSR) ovarian-cancer populations, regardless of their BRCAm status, support this. Long-term tolerability and efficacy of olaparib have been demonstrated in patients both with and without a BRCAm, with 13% of patients receiving maintenance olaparib for at least 5 years in one study, which is unprecedented in the relapsed ovarian-cancer setting (versus 1% on placebo). Further studies should be performed to elucidate which non-BRCAm patients are deriving benefit and what molecular processes are enabling this, so that patients continue to receive optimal treatment for their disease. Here, we review clinical and molecular markers of HRD, the long-term clinical safety and efficacy of PARP inhibitors in ovarian cancer, with a focus on olaparib and the current approved indications for PARP inhibitors, as well as guidance on treatment decisions for patients with PSR ovarian cancer.

Targeted treatment of advanced ovarian cancer: spotlight on rucaparib.

The last 2 years have ushered in a new era in ovarian cancer therapy with the US Food and Drug Administration’s (FDA) approval of poly-ADP ribose polymerase (PARP) inhibitors (PARPi). One of the deadliest cancers that women experience, ovarian cancer, is most often diagnosed in advanced stages. Although cytoreductive surgery and (platinum/taxane-based) chemotherapy can place the majority of patients into remission, most will experience a relapse of their disease in their lifetime. This has led to studies exploring the benefits and efficacy of maintenance treatment. This review will briefly discuss the history of maintenance therapy as well as focus on the FDA’s approval of rucaparib and its companion tumor profiling test, in the US. It will describe how women with deleterious mutations in the BRCA gene, through their inherent deficiency in homologous recombination, presented scientists with a target to exploit through a concept known as synthetic lethality. Not only did this lead to a targeted treatment for BRCA mutation carriers but for other patients with deficiencies in homologous recombination and, more broadly, also in platinum-sensitive patients. The focus of this review will be on rucaparib in the US, approved for both maintenance of platinum-sensitive recurrent ovarian cancer and treatment in the third-line setting and beyond. It has the broadest indication amongst the three PARPi in ovarian cancer. Furthermore, the ongoing trials using rucaparib in ovarian cancer and other disease types will be discussed.

The Role of PARP Inhibitors in Ovarian Cancer: An Emerging Picture

Dr Oaknin welcomed the delegates to the symposium and presented the objectives and agenda for the meeting as well as a case study presentation. Dr Birrer presented on the current landscape of platinum-sensitive recurrent ovarian cancer (PSR OC), including USA and European treatment guidelines. He highlighted data from three landmark Phase III studies that demonstrated the efficacy of platinum-based doublet therapy for patients with PSR OC. The role of cytoreductive surgery is still being debated but bevacizumab and a newer anti-angiogenic agent, cediranib, may both extend progression-free survival (PFS) in these patients. He predicted that new combinations of therapies will be tested. Prof Ledermann followed with a presentation on the role of poly(ADP-ribose) polymerase (PARP) inhibitors, olaparib, niraparib, and rucaparib, in the treatment of PSR OC. The largest increase in PFS is seen in patients with platinum-sensitive BRCA-mutant tumours but there is also significant benefit over placebo in groups of patients with platinum-sensitive BRCA wild-type tumours. Prof McNeish discussed the challenge of identifying the 30% of women with high-grade serous OC who would respond to treatment with a PARP inhibitor even though their tumour does not carry a BRCA mutation. Loss of heterozygosity (LOH) is a key indicator of homologous recombination deficiency (HRD) but current tests miss some women who would benefit from treatment. Dr Lorusso concluded the meeting by exploring future directions for research into PARP inhibitors, such as whether they should be used in the front-line setting and as single agents rather than in combination with chemotherapy. New combinations with anti-angiogenic and immune-oncology agents show promise, as does the potential for retreatment with a different PARP inhibitor.

Recent advances in targeting DNA repair pathways for the treatment of ovarian cancer and their clinical relevance.

Poly (ADP-ribose) polymerase (PARP) inhibitors have attracted much attention as one of the major molecular-targeted therapeutics for inhibiting DNA damage response. The PARP inhibitor, olaparib, has been clinically applied for treating certain recurrent ovarian cancer patients with BRCA1/2 mutations in Europe and the United States. It was also designated on 24 March 2017 as an orphan drug in Japan for similar clinical indications. In this review, we discuss (i) the prevalence of BRCA1/2 mutations in ovarian cancer, (ii) clinical trials of PARP inhibitors in ovarian cancer, (iii) genetic counseling for hereditary breast and ovarian cancer patients, and (iv) non-BRCA genes that may be associated with homologous recombination deficiency.

PARP inhibitors in ovarian cancer: evidence, experience and clinical potential.

Inhibitors of poly(ADP-ribose) polymerase (PARP) are considered one of the most active and exciting new therapies for the treatment of ovarian cancer. The anticancer activity of PARP inhibitors is based on the DNA repair vulnerability of many ovarian cancer cells, and multiple mechanisms of action of PARP inhibitors have been identified. As single agents, PARP inhibitors have demonstrated their greatest activity in ovarian cancer cells that harbor mutations in BRCA genes. Additionally, recent phase III studies have shown that single-agent PARP inhibitor activity extends beyond BRCA-related cancers and can benefit patients with ovarian cancers that do not have known BRCA mutations, especially when clinical characteristics such as platinum sensitivity and high-grade serous histology are present. PARP inhibitors have also been combined with chemotherapy, however, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations has hampered development of these combinations. Contrariwise, PARP inhibitor and biologic agent combinations, specifically antiangiogenic agents, appear well tolerated and show promising activity in both BRCA mutated (BRCAm) and BRCA wild-type (BRCAwt) cancers. Currently, multiple clinical trials are underway examining the antitumor activity of PARP inhibitor combination therapy.

The current status of PARP inhibitors in ovarian cancer.

Recent advances in our understanding of the molecular biology of epithelial ovarian cancer have led to the development of a number of targeted therapies, including poly-ADP-ribose polymerase (PARP) inhibitors. PARP inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Early studies have shown significant efficacy for PARP inhibitors in patients with germline BRCA1/2 mutations. It has become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this therapeutic approach. Importantly, companion homologous recombination deficiency scores are being developed to help guide the selection of patients most likely to gain clinical benefit from PARP inhibition. Olaparib, the first and most extensively investigated PARP inhibitor, is now licensed in Europe for maintenance treatment of patients with platinum-sensitive relapsed BRCA-mutated (germline or somatic) high-grade serous ovarian cancer who have responded to platinum-based chemotherapy. In the United States, olaparib is licensed for treatment of patients with germline BRCA-mutated ovarian cancer who have received 3 or more lines of chemotherapy. There are a number of other PARP inhibitors in late phase clinical development in ovarian cancer including rucaparib, niraparib, veliparib, and talazoparib. This review will focus on the current evidence for PARP inhibitors in ovarian cancer and discuss ongoing clinical trials and future research directions in this rapidly evolving area.

PARP inhibitors in ovarian cancer

Slow progress in improving the outcome of ovarian cancer with chemotherapy over the last decade has stimulated research into molecularly targeted therapy. Poly(ADP-ribose) polymerase (PARP) inhibitors target DNA repair and are specifically active in cells that have impaired repair of DNA by the homologous recombination (HR) pathway. Cells with mutated BRCA function have HR deficiency (HRD), which is also present in a significant proportion of non-BRCA-mutated ovarian cancer. In the last decade, olaparib, the first and most-investigated oral PARP inhibitor, has undergone phase I-III trials as a single agent, in comparison with and in addition to chemotherapy, and as a maintenance therapy following chemotherapy. The greatest benefit to-date has been in the maintenance setting, prolonging the progression-free survival of high-grade serous ovarian cancer with a BRCA1/2 mutation. In this group of patients, olaparib has received approval as maintenance following chemotherapy from the EMA, and accelerated approval as a single agent in women who have had three or more lines of therapy. Olaparib can be given for a prolonged period with few significant side-effects in most patients. Similar trials with other PARP inhibitors (rucaparib, niraparib and veliparib) are in progress and include non-BRCA-mutated ovarian cancer. Second-generation studies are exploring the combination of PARP inhibitors with anti-angiogenic drugs. PARP inhibitors represent a step change in the management of ovarian cancer. BRCA mutations are the first genotypic predictive markers in ovarian cancer and can be used to select patients who will most likely benefit from PARP inhibitors. BRCA testing is now becoming a routine part of the evaluation of women with ovarian cancer, and tests for HRD are being used to evaluate PARP inhibitors in an extended population of non-BRCA-mutated ovarian cancer.

The development of PARP inhibitors in ovarian cancer: from bench to bedside.

The nuclear enzyme poly (ADP-ribose) polymerase (PARP) represents an important novel target in the treatment of ovarian cancer. This article charts over 50 years of research from the discovery of the first PARP enzyme in 1963, to the approval and licensing in 2015 of the first PARP inhibitor, olaparib (Lynparza), in the treatment of BRCA-mutated ovarian cancer.

PARP inhibitors in ovarian cancer: Clinical evidence for informed treatment decisions.

Ovarian cancer is the fifth leading cause of female cancer deaths in the Western world. Significant progress has been made in the treatment of patients with ovarian cancer, however, the majority of patients experience disease recurrence and new therapies are being sought for such patients. Clinical investigation of poly(ADP-ribose) polymerase (PARP) inhibitors for ovarian cancer treatment has demonstrated promising activity in this disease. Here, we review the development of PARP inhibitors and their future role in the treatment of patients with ovarian cancer. Studies of olaparib, the first PARP inhibitor to be approved in Europe and the USA, in patients with recurrent ovarian cancer have demonstrated clinical efficacy with improvements in progression-free survival. In maintenance therapy of platinum-sensitive ovarian cancer there is supporting evidence of clinical benefit from exploratory endpoints that include time to first subsequent treatment and time to second subsequent treatment. Adverse events that should be monitored following treatment with PARP inhibitors include nausea, vomiting, fatigue and anaemia. Based on the evidence presented, patients who will receive the greatest benefit from PARP inhibition are those with platinum-sensitive relapsed ovarian cancer and a BRCA mutation.

Targeting DNA repair: poly (ADP-ribose) polymerase inhibitors

Ovarian cancer represents a significant challenge in women’s health, with an estimated 21,980 new cases and 14,270 deaths in the United States in the year 2014. Despite excellent response rates to cytotoxic chemotherapy, the majority of patients will relapse within two to three years and extending their remission through consolidation remains a priority. The development of novel treatment agents is therefore imperative. Poly (ADP-ribose) polymerase (PARP) inhibitors are a promising new class of targeted agents currently in clinical trials for ovarian cancer. PARP inhibitors were first studied in patients harboring BRCA1/2 mutations due to the known synthetic lethality of BRCA1/2 -associated dysfunctional homologous recombination (HR) DNA repair and PARP inhibitor-associated loss of base excisional repair (BER) and non-homologous end rejoining. However, preclinical and emerging clinical data suggest that PARP inhibitors may benefit a broader patient population. While the initial studies of PARP inhibitors in ovarian cancer are encouraging, there remain many unanswered questions including the ideal timing of administration, whether to give these drugs as monotherapy or in combination with other antineoplastic agents and how to identify the patients most likely to respond. The focus of this review will be on the underlying mechanism of PARP inhibition in cancer, preclinical data, current clinical trials and the future of PARP inhibitors in the treatment of ovarian cancer.

PARP Inhibitors in BRCA Gene-Mutated Ovarian Cancer and Beyond

Poly(ADP-ribose)polymerase (PARP) inhibitors are showing considerable promise for the treatment of BRCA mutation-associated ovarian and breast cancer. This approach exploits a synthetic lethal strategy to target the specific DNA repair pathway in cancers that harbor mutations in the BRCA1 or BRCA2 genes. Accumulating evidence suggests that PARP inhibitors may have a wider application in the treatment of sporadic, high-grade serous ovarian cancers and other cancers including endometrial cancer. In this review, we discuss the clinical development of PARP inhibitors in ovarian cancer and explore challenges that need to be addressed if the full potential of these agents is to be realized.