Meta-analysis on the PARP-inhibitor olaparib reveals therapeutic efficacy in ovarian cancer independent of BRCA1/2 mutation status

Abstract

Poly(ADP-ribose) polymerase (PARP) inhibitors are one of the most promising drugs for ovarian cancer treatment. This study investigated clinical trials of PARP inhibitors, in order to obtain a more complete prognosis of ovarian cancer patients, which is usually dependent on their BRCA1/2 mutation status. The PubMed database was searched using the key terms "PARP inhibitor OR olaparib OR veliparib OR niraparib OR rucaparib OR (BMN 673) AND (ovarian cancer OR solid tumors)", while narrowing the selection of the article type to "clinical trial" only. Women included in the study had been histologically diagnosed with recurrent high-grade serous ovarian-, fallopian tube-or primary peritoneal-carcinoma, regardless of the presence of BRCA germline mutation or platinum-sensitive disease recurrence. Data from three Phase I and eight Phase II clinical trials were obtained, two of which evaluated veliparib, eight olaparib and one niraparib. A total of 1042 patients with either high-grade serous ovarian-, fallopian tube-or primary peritoneal cancer were enrolled, of which 587 had a BRCA1/2 germline mutation and at least 370 were platinum-sensitive. The overall response rate (ORR) for patients who underwent treatment with olaparib was 44.5% (95% confidence interval = 0.396-0.496). Patients with BRCA1/2 mutation and those with wild-type BRCA1/2 showed no significant difference in ORR (p = 0.35), even when considering solely Phase II trials (p = 0.13). PARP inhibitors, particularly olaparib, proved effective in the management of ovarian cancer patients. This study identified the existence of patients who presented wild-type BRCA1/2 and possibly BRCA-independent homologous-recombination deficient tumors, or patients with wild-type BRCA1/2 and tumors presenting other forms of BRCAness, who benefit from treatment with olaparib.

Ovarian carcinoma: An overview of current status

“…Poly(ADP-ribose) polymerase (PARP) inhibitors have been approved by the US Food and Drug Administration (FDA) as a monotherapy in patients previously treated with chemotherapy, and the inhibitors have also shown synergistic action with anti-angiogenic agents due to oxygenation changes. The use of these inhibitors has opened up a whole new treatment option for BRCA-deficient ovarian cancer patients in the US and Europe [99,100] . The suppression of PTTG1 (pituitary tumor transforming gene) expression and the activation of p53 expression were shown by DNA-damaging drugs (doxorubicin and bleomycin), which induce cell cycle arrest to repair the damaged DNA.…”