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

ABSTRACT: 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.

SUBMITTER: Ledermann JA

PROVIDER: S-EPMC4816268 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

Ledermann Jonathan A JA El-Khouly Fatima F

British journal of cancer 20151201

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 ...[more]

PMID: 26669450

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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.

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

Publications

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

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