The Role of PARP Inhibitors in the Treatment of Prostate Cancer: Recent Advances in Clinical Trials

Abstract

Poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis) belong to a class of targeted drugs developed for the treatment of homologous recombination repair (HRR)-defective tumors. Preclinical and limited clinical data suggest that PARP inhibition is effective against prostate cancer (PC) in patients with HRR-deficient tumors and that PARPis can improve the mortality rate of PC in patients with BRCA1/2 mutations through a synthetic lethality. Olaparib has been approved by the FDA for advanced ovarian and breast cancer with BRCA mutations, and as a maintenance therapy for ovarian cancer after platinum chemotherapy. PARPis are also a new and emerging clinical treatment for metastatic castration-resistant prostate cancer (mCRPC). Although PARPis have shown great efficacy, their widespread use is restricted by various factors, including drug resistance and the limited population who benefit from treatment. It is necessary to study the combination of PARPis and other therapeutic agents such as anti-hormone drugs, USP7 inhibitors, BET inhibitors, and immunotherapy. This article reviews the mechanism of PARP inhibition in the treatment of PC, the progress of clinical research, the mechanisms of drug resistance, and the strategies of combination treatments.

METTL3 promotes homologous recombination repair and modulates chemotherapeutic response in breast cancer by regulating the EGF/RAD51 axis

“…A large number of studies have implicated dysfunctional DNA repair proteins, such as BRCA1, RAD51, FEN1, and Polβ, in BC initiation and progression ( Li et al, 2021 ; Lu et al, 2020 ; Martin et al, 2007 ; Thacker, 2005 ; Wang et al, 2019 ; Wang et al, 2020b ; Xia et al, 2021 ). Elevated DNA repair activity contributes to drug resistance and limits the efficacy of chemotherapeutic agents ( Long et al, 2021 ; Lu et al, 2020 ).…”

“…Thus, targeting the DDR key proteins such as BRCA1 and BRCA2 is a potential effective therapeutic strategy for mono- or combination therapy. In 2005, the synthetic lethality between PARP inhibition and BRCA1 or BRCA2 mutation was reported by two independent groups, suggesting a novel strategy for treating patients with BRCA-mutant tumors ( Bryant et al, 2005 ; Farmer et al, 2005 ; Xia et al, 2021 ). Inhibition of PAPR1 causes failure of DNA single-stranded breaks repair, finally leading to DSBs in cells.…”

BRCA Mutations in Prostate Cancer: Assessment, Implications and Treatment Considerations

“…Use of PARP inhibitors has shown particularly favorable outcomes in BRCA1/2 mutations with increased survival outcomes [ 142 ]. Olaparib has a good curative effect and is used in prostate cancer with BRCA mutations that progressed following novel hormonal agents, e.g., enzalutamide or abiraterone; Rucaparib is used in combination with AR guided therapy and paclitaxel-based chemotherapy in mCRPC with harmful BRCA mutations [ 143 , 144 ]. The fact that a fraction of biomarker-negative patients respond to PARP inhibitors is indicative of undetected DDR mutations that may exist in genomic regions less effectively covered by NGS.…”

PARP-1 Expression and BRCA1 Mutations in Breast Cancer Patients’ CTCs

“…In the HR-deficient (BRCA-mutated) cells, however, it will result in a DSB, when this SSB reaches the replication fork. Accumulation of DSBs will prove fatal for the cell as they will lead to cell apoptosis or accumulation of mutations with higher likelihood for cancer development [ 5 , 21 , 22 , 23 , 24 ].…”