PARP Inhibitors in Metastatic Prostate Cancer: A Comprehensive Systematic Review and Meta-analysis of Existing Evidence - Beyond the Abstract
Among these, PARP inhibitors (PARPi) have shown effectiveness in cancers associated with mutations in DNA repair genes, such as BRCA1, BRCA2, and ATM, through a synthetic lethality mechanism. Olaparib and rucaparib received FDA and EMA approval in the metastatic castration-resistant setting (mCRPC). Meanwhile, other agents such as niraparib, talazoparib, and veliparib are currently under investigation. However, given their novelty, several issues about their use are still pending: the safety profile, the prediction of response, possible combination therapies, and their anticipation at earlier stages of PCa before the onset of castration resistance.
We conducted a systematic review and meta-analysis to examine the oncological outcomes and safety profile of PARP inhibitor (PARPi) treatment in metastatic castration-resistant prostate cancer (mCRPC) patients. Our goal was to better understand the current and potential future roles of this class of drugs in the treatment of prostate cancer.
From a methodological standpoint, retrospective studies were included in the meta-analysis when higher-quality evidence about outcomes of interest was lacking. Notably, randomized controlled trials are not available for every molecule under consideration; they are limited to olaparib. The absence of high-level data for several other PARP inhibitors meant that not all research questions could be addressed using prospective data only. Therefore, we opted to incorporate retrospective data in the meta-analysis, even though this decision may lead to a loss of quality.
This decision further underscores the persisting uncertainties surrounding specific outcomes of interest, highlighting the imperative for future, well-designed prospective trials. However, our findings indicate that PARPi has different potential applications in mCRPC, either administered independently or in combination with other molecules. These results are not limited to Olaparib, but all the molecules obtain good responses in mCRPC patients. This observation extends beyond Olaparib, as all the molecules demonstrate favorable responses in mCRPC patients. The most notable advantages are evident in patients with mutations in HR genes, particularly those carrying BRCA2 gene mutations.
An open issue, persisting after our analysis, pertains to the optimal timing of administering these drugs and the feasibility of introducing this therapeutic approach at earlier disease stages. Despite the heavily pretreated nature of all included patients, we were unable to conduct a formal meta-analysis on this matter due to the lack of data on previous treatments before the initiation of PARPi in most studies.
The need for effective therapies is compelling, as patients with mCRPC continue to face a poor prognosis despite the growing understanding of PCa's pathophysiology. These results underline the potential of targeted therapies tailored to patients' genetic and emphasize the potential benefits of combination regimens.
Written by: Francesco Ditonno, MD, Alessandro Veccia, MD, & Alessandro Antonelli, MD
Department of Urology, University of Verona, Verona, Italy
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