Do PARP inhibitors improve survival in women with ovarian cancer and what are the side effects?

Background
Conventional chemotherapy drugs act on dividing cells by damaging cell DNA. As cancer cells divide very rapidly, these drugs affect cancer cells to a greater degree than normal cells. Being able to repair DNA is vital to cell survival and normal cells have more than one DNA repair systems. However, cancer cells often have defects in these repair pathways that makes them harder for them to repair themselves. PARP inhibitors are a new type of medication that works by preventing cancer cells from repairing their DNA once they have been damaged by chemotherapy.

Review question
Do PARP inhibitors improve survival in women with epithelial ovarian cancer and what are the side effects?

Main results
We searched the literature from 1990 to April 2015 and found four randomised trials of PARP inhibitors versus other treatments or placebo. We also found four ongoing studies. The four completed studies included 599 women with recurrent epithelial ovarian cancer; three included women with platinum-sensitive disease (return of disease more than 12 months since last chemotherapy treatment), and one included women with platinum-resistant and partially platinum-sensitive disease (return of disease less than six months or six to 12 months since last chemotherapy treatment). Three studies all tested a PARP inhibitor known as olaparib and one study with only 75 patients tested veliparib. On average, when added to conventional treatment, olaparib slowed the progression of disease in women with platinum-sensitive disease compared with placebo or no added treatment, but did not alter the time that patients survived, although there were relatively few women in the studies and larger studies may change this outcome. Adverse events of any severity were common in both the PARP inhibitor group and the control group. However, serious adverse events were more common in the olaparib group than the control group when given as maintenance treatment after a course of chemotherapy. The most common serious adverse events were anaemia and fatigue. Data for veliparib were limited, due to the small number of women included, so we were unable to show if it had any effect on the progression of the disease. Veliparib had few severe side effects, but again the numbers were too small for meaningful conclusions.

Quality of the evidence
The evidence is of moderate quality for studies looking at the affects of olaparib and estimates of effect may change with further research. There was low quality evidence for veliparb and we are very uncertain about the effects of the treatment.

Authors' conclusions: 

PARP 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.

Read the full abstract...
Background: 

Ovarian 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.

Objectives: 

To determine the benefits and risks of PARP inhibitors for the treatment of epithelial ovarian cancer (EOC).

Search strategy: 

We identified randomised controlled trials (RCTs) by searching the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 3), the Cochrane Gynaecological Cancer Group Trial Register, MEDLINE (1990 to April 2015), EMBASE (1990 to April 2015), 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 criteria: 

Women 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 analysis: 

We 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 results: 

We 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. Adverse events of any severity were common in both the PARP inhibitor group and the control group. 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; high quality evidence). Quality of life data were insufficient for meta-analysis. We identified four ongoing studies.

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