Advances in PARP Inhibitors for Prostate Cancer

Abstract

Poly-adenosine diphosphate-ribose polymerase plays an essential role in cell function by regulating apoptosis, genomic stability and DNA repair. PARPi is a promising drug class that has gained significant traction in the last decade with good outcomes in different cancers. Several trials have sought to test its effectiveness in metastatic castration resistant prostate cancer (mCRPC). We conducted a comprehensive literature review to evaluate the current role of PARPi in this setting. To this effect, we conducted queries in the PubMed, Embase and Cochrane databases. We reviewed and compared all major contemporary publications on the topic. In particular, recent phase II and III studies have also demonstrated the benefits of olaparib, rucaparib, niraparib, talazoparib in CRPC. Drug effectiveness has been assessed through radiological progression or overall response. Given the notion of synthetic lethality and potential synergy with other oncological therapies, several trials are looking to integrate PARPi in combined therapies. There remains ongoing controversy on the need for genetic screening prior to treatment initiation as well as the optimal patient population, which would benefit most from PARPi. PARPi is an important asset in the oncological arsenal for mCRPC. New combinations with PARPi may improve outcomes in earlier phases of prostate cancer.

IGFBP3 promotes resistance to Olaparib via modulating EGFR signaling in advanced prostate cancer

“…Poly(ADP-ribose) polymerase inhibitors (PARPi) are a revolutionary class of targeted therapeutics that weaponizes the tumor cell’s homologous recombination (HR) defects by disrupting PARP’s function to repair DNA breaks. 14 , 15 This approach selectively kills tumor cells with HR defects while sparing the patient’s nonmalignant cells, in a process termed synthetic lethality. 16 The landmark battles of 2005 discovered that epithelial cancers lacking germline BRCA1, BRCA2, and ATM struggle to repair double-strand DNA breaks (DSBs) due to the cancer cell’s inability to perform homology-directed DNA repair, thus are vulnerable to DNA damage.…”

PACT is requisite for prostate cancer cell proliferation

“…Immunotherapy (e.g., sipuleucel-T), and management of bone metastasis with bone-targeted therapy (e.g., radium-233), have also provided survival bene ts for patients with . Recent advances in systemic therapies for the effective treatment of CRPC include targeting the highly expressed prostate-speci c membrane antigen (PSMA) with radioligand therapy i.e., 177 Lu-PMSA-617, polyadenosine diphosphate-ribosome polymerase inhibitors (PARPi) e.g., Talazoparib (11)(12)(13), and ultrasound therapy, particularly when combined with anticancer drugs contained within or on 'microbubbles' or targeted nanobubbles to PSMA for targeted drug delivery and release (14)(15)(16)(17). Despite these advances in treatment options for CRPC, the disease remains incurable, emphasizing the unmet clinical need for new PCa therapeutics.…”

PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer: Unraveling the Therapeutic Landscape

“…Life 2024, 14,198 2 of 14 Poly-ADP ribose polymerases (PARPs) are nuclear enzymes that are involved in repairing single-strand breaks (SSBs) in the DNA, while double-strand breaks (DSBs) are repaired through either HRR or non-homologous end joining (NHEJ). PARP inhibitors (PARPis) are targeted drugs that inhibit the DNA-repairing mechanism of PARPs and are lethal in tumors harboring HRR mutations (HRRms) [11].…”

“…Particularly, BRCA1 and BRCA2, which act downstream the PARP1 cascade in one of the two major pathways for DSB repair, are crucial for maintaining genomic integrity. Therefore, cells with germline/somatic BRCA1/BRCA2 mutations are highly vulnerable to PARPis [13,14]. Herein, we review recent results from key phase III trials evaluating PARPis in patients with mCRPC.…”