Simple SummaryRecent genomic analytical advancements have revealed thatBRCA1/2pathogenic variants are the most frequent mutations among DNA damage repair genes in prostate cancer. Polyadenosine diphosphatase ribose polymerase (PARP) inhibitor, olaparib, has been shown as an effective therapeutic option for the disease. This review focuses on PARP inhibitors’ basic and clinical mechanisms of action against prostate cancer and discusses their effects on the tumor microenvironment.AbstractCancer cells frequently exhibit defects in DNA damage repair (DDR), leading to genomic instability. Mutations in DDR genes or epigenetic alterations leading to the downregulation of DDR genes can result in increased dependency on other DDR pathways. Therefore, DDR pathways could be a treatment target for various cancers. In fact, polyadenosine diphosphatase ribose polymerase (PARP) inhibitors, such as olaparib (Lynparza®), have shown remarkable therapeutic efficacy againstBRCA1/2-mutant cancers through synthetic lethality. Recent genomic analytical advancements have revealed thatBRCA1/BRCA2pathogenic variants are the most frequent mutations among DDR genes in prostate cancer. Currently, the PROfound randomized controlled trial is investigating the efficacy of a PARP inhibitor, olaparib (Lynparza®), in patients with metastatic castration-resistant prostate cancer (mCRPC). The efficacy of the drug is promising, especially in patients withBRCA1/BRCA2pathogenic variants, even if they are in the advanced stage of the disease. However, olaparib (Lynparza®) is not effective in allBRCA1/2mutant prostate cancer patients and inactivation of DDR genes elicits genomic instability, leading to alterations in multiple genes, which eventually leads to drug resistance. In this review, we summarize PARP inhibitors’ basic and clinical mechanisms of action against prostate cancer cells and discuss their effects on the tumor microenvironment.