Abstract
Simple SummaryPoly (ADP-ribose) polymerase inhibitors (PARPis; inhibitors of a family of enzymes that are primary involved in DNA repair) are considered to be the drug of choice in maintenance therapy for platinum-sensitive ovarian cancer. However, despite the FDA approval of three such agents and their availability in clinical practice, thus far, no clinical trial investigated them in a head-to-head direct comparison. In this study, we used a statistical approach that allows comparing direct and indirect evidence (network meta-analysis) in order to compare the three FDA-approved PARPis (olaparib, niraparib and rucaparib). To this end, we used data from six randomized control trials involving a total of 2270 ovarian cancer patients. Interestingly, we found no significant differences in clinical outcomes (overall survival and progression-free survival) between the three agents. However, niraparib was found to be associated with higher risk of certain adverse events (thrombocytopenia, neutropenia, constipation, and headaches) compared to the other two PARPis.Background: Three PARPis (olaparib, niraparib and rucaparib) are currently FDA-approved as maintenance therapy in newly diagnosed and recurrent ovarian cancer. However, thus far, no trial has compared the three approved PARPis in the overall population, in patients with BRCA mutations, or in those with wild-type BRCA. Methods: A frequentist network meta-analysis was used for indirect comparisons between the different PARPis with respect to progression free survival (PFS), overall survival (OS), and adverse events. Results: Overall, six randomized clinical trials involving 2,770 patients, were included in the analysis. Results from the indirect comparisons revealed no statistically significant differences between the three PARPis with respect to PFS or OS in the entire population and in patients with mutated and wild-type BRCA, separately. Niraparib showed a statistically significant increased risk for grade 3 and 4 thrombocytopenia (risk-difference [RD] from placebo: 0.3; 95% confidence interval [CI], 0.27‒0.34) and any grade neutropenia (RD from placebo: 0.22; 95% CI, 0.18‒0.25) as compared with the other PARPis. Conclusion: No statistically significant difference was found between the three PARPis with respect to PFS or OS (overall and in subpopulations by BRCA status). There is, however, a statistical difference in toxicity as niraparib is associated with a greater risk for thrombocytopenia and neutropenia.
Highlights
Ovarian cancer is one of the leading causes of cancer death in women and the most common gynecologic cancer worldwide [1]
Poly(ADP-ribose) polymerase (PARP) is a family of enzymes that are primarily involved in detecting single-strand DNA breaks, and trigger a cascade of events leading to DNA repair [5]
With respect to adverse events (AEs), statistically significant differences were observed, with niraparib being associated with a higher risk of thrombocytopenia and neutropenia compared to the other Poly (ADP-ribose) polymerase inhibitors (PARPis), more constipation and more headaches
Summary
Ovarian cancer is one of the leading causes of cancer death in women and the most common gynecologic cancer worldwide [1]. Adding PARP inhibitors (PARPis) to the treatment regimen promotes cancer cell death [6] This mechanism of action paired with the centrality of BRCA proteins in the process of DNA repair resulted in the presumption that PARPis were primarily of value in tumors with a BRCA1 or BRCA2 mutations [7]. While this has since been proven to be the case, it has become evident that. Results from the indirect comparisons revealed no statistically significant differences between the three PARPis with respect to PFS or OS in the entire population and in patients with mutated and wild-type BRCA, separately. Niraparib showed a statistically significant increased risk for grade 3 and 4 thrombocytopenia
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