Over the last decade, there has been a considerable advancement in the treatment of metastatic prostate cancer. Palliative therapy care has traditionally included androgen deprivation, chemotherapy, and other radiation treatment techniques. Recently, breakthrough therapy with poly-ADP-ribose polymerase (PARP) inhibitors has resulted in a considerable improvement in the outcome of individuals with metastatic prostate cancer who have particular genetic alterations. This brief study focuses on the three PARP inhibitors that have been found to be effective in metastatic prostate cancer.
What are PARP inhibitors
Poly-ADP-ribose polymerases (PARPs) are a class of enzymes that catalyze ADP-ribose transfer to target proteins. PARPs are essential in various of biochemical pathways, including transcription, replication, recombination, cell proliferation, and, most vitally, DNA repair. The discovery that both DNA damaging chemicals and radiation-induced DNA damage enhanced PARP activity provides evidence for the relevance of PARP in DNA repair.
Mode of mechanism
PARP1, the most well-known enzyme in this family, is critical in the detection and repair of DNA breaks. PARP1 synthesizes poly-ADP-ribose (PAR) and transfers it to acceptor proteins after detecting and binding to locations of single strand DNA damage. It then directs the recruitment of other essential repair enzymes to the damaged DNA spot. PARP1 has also been shown to be a rate limiting step in both base-excision repair (BER) and nucleotide-excision repair (NER). Since research has demonstrated that BER and NER are critical processes for repairing DNA damage produced by certain alkylating and chemotherapeutic drugs.
Recent investigations on PARP
PARP overexpression is one of the processes through which tumor cells might develop resistance to cancer treatment. In contrast, investigations have demonstrated that treating PARP/ mice with alkylating agents or Y-irradiation results in severe genomic instability and great susceptibility to both agents. As a result, because PARPs are essential for DNA repair, down-regulating or inhibiting PARP has the potential to improve tumor cell sensitivity to many kinds of anti-cancer therapy. Because PARP is involved in DNA repair, inhibiting it causes greater genomic instability as well as the buildup of damaged cells in cell cycle arrest. Experiments have shown how ADP-ribosylation processes are utilized to repair damaged DNA as well as advance through the G2 and M stages of the cell cycle. As a result, PARP inhibition makes highly susceptible to DNA damage.
Evaluation of the Efficacy of PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer
In August 2020, PubMed, Scopus, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science were searched for phase II/III clinical trials on PARP inhibitors in patients with mCRPC. Their findings revealed that individuals with mCRPC who had mutations in genes associated to the HR DNA repair pathway are more likely to benefit from PARP inhibitor therapy.
Rucaparib was granted accelerated approval by the FDA on May 15, 2020, for patients with deleterious BRCA mutation associated metastatic castration resistant prostate cancer (mCRPC) who had previously been treated with both androgen receptor-directed therapy and taxane-based chemotherapy.
Olaparib was authorized by the FDA on May 19, 2020, for the treatment of adult patients with germline or somatic HRR gene mutated metastatic castration resistant prostate cancer (mCRPC) who had progressed following previous therapy with enzalutamide.
Although it has not yet been licenced by the FDA, the other major PARP inhibitor that has lately showed remarkable promise in the treatment of PCa is niraparib
Conclusion and future prospects
Moving forward, it will be critical to determine if PARP inhibition can be more successful when paired with other anti-cancer therapies. Future research must also focus on the negative effects and contraindications of PARP inhibitors. It will also be vital to explore the possibility of cancer return years following therapy. Nonetheless, targeted therapy through PARP inhibition could have the ability to revolutionize the treatment of mCRPC.