Bin Feng

Potential Synergistic Effect between Niraparib and Statins in Ovarian Cancer Clinical Trials

Abstract This study investigates the potential clinical synergy between the PARP inhibitor niraparib (Zejula) and concomitant statins, exploring their combined effects on progression-free survival (PFS) in patients with ovarian cancer. We retrospectively analyzed niraparib registrational clinical trials in ovarian cancer to investigate potential interactions between niraparib and statins. In the PRIMA trial, patients receiving niraparib demonstrated improved PFS compared with those on placebo (HR = 0.62; P < 0.001; median PFS 13.8 vs. 8.2 months). The post hoc analysis revealed that patients receiving maintenance niraparib who reported concomitant use of statins exhibited significantly improved PFS compared with those on placebo with concomitant statins (HR = 0.34; P < 0.001; median PFS 18.2 vs. 6.0 months). Notably, the improved efficacy in the two-arm comparison of concomitant statin patients was much better than that in the two-arm comparison of those patients without statin, as reflected in the niraparib–statin interaction (P = 0.005). These findings suggest novel opportunities in oncology for the use of statins in combination therapies with PARP inhibitors and emphasize the need for further investigation. Significance: The presented retrospective analysis suggests, to the best of our knowledge for the first time, a potential significant interaction between statins and niraparib in clinical settings. Nevertheless, further investigations are required to gain a better understanding of the potential clinical benefit.

Synergistic Effects of PARP Inhibition and Cholesterol Biosynthesis Pathway Modulation

Abstract An in-depth multiomic molecular characterization of PARP inhibitors revealed a distinct poly-pharmacology of niraparib (Zejula) mediated by its interaction with lanosterol synthase (LSS), which is not observed with other PARP inhibitors. Niraparib, in a similar way to the LSS inhibitor Ro-48-8071, induced activation of the 24,25-epoxysterol shunt pathway, which is a regulatory signaling branch of the cholesterol biosynthesis pathway. Interestingly, the combination of an LSS inhibitor with a PARP inhibitor that does not bind to LSS, such as olaparib, had an additive effect on killing cancer cells to levels comparable with niraparib as a single agent. In addition, the combination of PARP inhibitors and statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, an enzyme catalyzing the rate-limiting step in the mevalonate pathway, had a synergistic effect on tumor cell killing in cell lines and patient-derived ovarian tumor organoids. These observations suggest that concomitant inhibition of the cholesterol biosynthesis pathway and PARP activity might result in stronger efficacy of these inhibitors against tumor types highly dependent on cholesterol metabolism. Significance: The presented data indicate, to our knowledge, for the first time, the potential benefit of concomitant modulation of cholesterol biosynthesis pathway and PARP inhibition and highlight the need for further investigation to assess its translational relevance.