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New treatment option for ovarian cancer: PARP inhibitors.

ABSTRACT: Poly(ADP-ribose) polymerase (PARP), which was first described over 50 years ago by Mandel, are a family of protein enzymes involved in DNA damage response and works by recognizing the single-strand DNA break (ssDNA) and then effecting DNA repair. A double-strand DNA (dsDNA) break can be repaired by one of two different pathways: homologous recombination (HR) or non-homologous end joining (NHEJ). Homologous recombination occurs in the G2 or M phase of the cell cycle when a sister chromatid is available to use as a template for repair. Because a template is available, HR is a high fidelity, error-free form of DNA repair. With NHEJ there is not a template and the DNA is trimmed and ligated which is a very error-prone process of repair which can lead to genetic instability. Exploiting these mechanism led to development of PARP inhibitors with the idea of utilizing synthetic lethality, where two deficiencies each having no effect on the cellular outcome become lethal when combined, as single agent in BRCA deficient patients or as chemotherapy/radiotherapy combinations to inhibit ssDNA repair. The recent approval of olaparib in BRCA deficient ovarian cancer patients in US and Europe has opened up a whole new treatment option for ovarian cancer patients. This review will discuss the different PARP inhibitors in development and the potential use of this class of agents in the future.

SUBMITTER: Meehan RS

PROVIDER: S-EPMC4880823 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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New treatment option for ovarian cancer: PARP inhibitors.

Meehan Robert S RS Chen Alice P AP

Gynecologic oncology research and practice 20160226

Poly(ADP-ribose) polymerase (PARP), which was first described over 50 years ago by Mandel, are a family of protein enzymes involved in DNA damage response and works by recognizing the single-strand DNA break (ssDNA) and then effecting DNA repair. A double-strand DNA (dsDNA) break can be repaired by one of two different pathways: homologous recombination (HR) or non-homologous end joining (NHEJ). Homologous recombination occurs in the G2 or M phase of the cell cycle when a sister chromatid is ava ...[more]

PMID: 27231574

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Project description:BackgroundOvarian cancer is the sixth most common cancer and seventh most common cause of cancer death in women world-wide. Three-quarters of women present when the disease has spread throughout the abdomen (stage III or IV) and treatment consists of a combination of debulking surgery and platinum-based chemotherapy. Although initial responses to chemotherapy are good, most women will relapse and require further chemotherapy and will eventually develop resistance to chemotherapy.PARP (poly (ADP-ribose) polymerase) inhibitors, are a novel type of medication that works by preventing cancer cells from repairing their DNA once they have been damaged by other chemotherapy agents. It is not clear how PARP inhibitors compare to conventional chemotherapy regimens for the treatment of ovarian cancer, with respect to survival, side effects and quality of life.ObjectivesTo determine the benefits and risks of PARP inhibitors for the treatment of epithelial ovarian cancer (EOC).Search methodsWe identified randomised controlled trials (RCTs) by searching the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 4), the Cochrane Gynaecological Cancer Group Trial Register, MEDLINE (1990 to May 2014), EMBASE (1990 to May 2014), ongoing trials on www.controlled-trials.com/rct, www.clinicaltrials.gov, www.cancer.gov/clinicaltrials and the National Research Register (NRR), the FDA database and pharmaceutical industry biomedical literature.Selection criteriaWomen with histologically proven EOC who were randomised to treatment groups in trials that either compared PARP inhibitors with no treatment, or PARP inhibitors versus conventional chemotherapy, or PARP inhibitors together with conventional chemotherapy versus conventional chemotherapy alone.Data collection and analysisWe used standard Cochrane methodology. Two review authors independently assessed whether studies met the inclusion criteria. We contacted investigators for additional data, where possible. Outcomes included survival, quality of life and toxicity.Main resultsWe included four RCTs involving 599 women with EOC. Data for veliparib were limited and of low quality, due to small numbers (75 women total). Olaparib, on average, improved progression-free survival (PFS) when added to conventional treatment and when used as maintenance treatment in women with platinum-sensitive disease compared with placebo (hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.29 to 0.60; 426 participants ; two studies), but did not improve overall survival (OS) (HR 1.05, 95% CI 0.79 to 1.39; 426 participants; two studies). We graded this evidence as moderate quality using the GRADE approach. Olaparib was associated with more severe adverse events (G3/4) during the maintenance phase compared with controls (risk ratio (RR) 1.74, 95% CI 1.22 to 2.49; 385 participants, two studies; moderate quality evidence). Quality of life data were insufficient for meta-analysis. We identified four ongoing studies.Authors' conclusionsPARP inhibitors appear to improve PFS in women with recurrent platinum-sensitive disease. Ongoing studies are likely to provide more information about whether the improvement in PFS leads to any change in OS in this subgroup of women with EOC. More research is needed to determine whether PARP inhibitors have any role to play in platinum-resistant disease.

Project description:PurposeTo provide recommendations on the use of poly(ADP-ribose) polymerase inhibitors (PARPis) for management of epithelial ovarian, tubal, or primary peritoneal cancer (EOC).MethodsRandomized, controlled, and open-labeled trials published from 2011 through 2020 were identified in a literature search. Guideline recommendations were based on the review of the evidence, US Food and Drug Administration approvals, and consensus when evidence was lacking.ResultsThe systematic review identified 17 eligible trials.RecommendationsThe guideline pertains to patients who are PARPi naïve. All patients with newly diagnosed, stage III-IV EOC whose disease is in complete or partial response to first-line, platinum-based chemotherapy with high-grade serous or endometrioid EOC should be offered PARPi maintenance therapy with niraparib. For patients with germline or somatic pathogenic or likely pathogenic variants in BRCA1 (g/sBRCA1) or BRCA2 (g/sBRCA2) genes should be treated with olaparib. The addition of olaparib to bevacizumab may be offered to patients with stage III-IV EOC with g/sBRCA1/2 and/or genomic instability and a partial or complete response to chemotherapy plus bevacizumab combination. Maintenance therapy (second line or more) with single-agent PARPi may be offered for patients with EOC who have not received a PARPi and have responded to platinum-based therapy regardless of BRCA mutation status. Treatment with a PARPi should be offered to patients with recurrent EOC that has not recurred within 6 months of platinum-based therapy, who have not received a PARPi and have a g/sBRCA1/2, or whose tumor demonstrates genomic instability. PARPis are not recommended for use in combination with chemotherapy, other targeted agents, or immune-oncology agents in the recurrent setting outside the context of a clinical trial. Recommendations for managing specific adverse events are presented. Data to support reuse of PARPis in any setting are needed.Additional information is available at www.asco.org/gynecologic-cancer-guidelines.

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New treatment option for ovarian cancer: PARP inhibitors.

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New treatment option for ovarian cancer: PARP inhibitors.

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