The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies

Abstract

As cells age and are exposed to genotoxic stress, preservation of the genomic code requires multiple DNA repair pathways to remove single or double- strand breaks. Loss of function somatic genomic aberrations or germline deficiency in genes involved in DNA repair can result in acute cell death or following a latency period cellular transformation. Therapeutic exploitation of DNA repair by inhibition of poly (adenosine diphosphate [ADP]) ribose polymerases (PARP), a family of enzymes involved in the repair of single-strand and in some cases double-strand breaks, has become a novel cancer treatment. While the application of PARP inhibitors (PARPis) was initially focused on tumors with BRCA1 or BRCA2 deficiency, our current knowledge has extended synthetic susceptibilities of PARPi to deficiencies in proteins and pathways involved in DNA damage repair (DDR) in particular those that repair double-strand breaks using homologous recombination (HR). There is an increasing appreciation that genitourinary (GU) malignancies, including bladder, and especially prostate cancers, contain subsets of patients with germline and somatic alterations in HR genes that may reflect increased response to PARPis. In this review, we describe the mechanisms and rationale of PARPi use in GU cancers, summarize previously reported pre-clinical and clinical trials, and identify ongoing trials to determine how PARPis and strategies targeted at HR repair can be applied for widespread application in GU cancers.

Development of PARP and Immune-Checkpoint Inhibitor Combinations

“…In particular, patients harboring tumors with high levels of genomic scarring, such as LOH suggestive of a defect in DDR (9, 10), or whose tumors have mutations in other, non-BRCA1/2, DDR genes (13). Defects in DDR genes are present across a broad range of tumor types, including prostate, bladder (14), pancreatic (15), and non-small cell lung (16) cancers, and clinical trials of PARP inhibitors are ongoing in many of these settings.…”

Current Strategies and Novel Therapeutic Approaches for Metastatic Urothelial Carcinoma

“…In fact, in multiple tumors the presence of DDR gene aberrations correlates with an enhanced sensibility to platinum compounds [134]. Based on these results, PARP inhibitors have been studied in UC as well [135][136][137][138]. At the recent ASCO Genitourinary Cancers Symposium 2020, the results of the study ATLAS (NCT03397394) were presented [134].…”

Cancer Genetics and Therapeutic Opportunities in Urologic Practice

“…There are currently four FDA-approved PARP inhibitors (olaparib, rucaparib, niraparib, talazoparib) for other gBRCAm cancers including ovarian and breast [60][61][62][63][64][65]. These drugs have shown significant survival advantages in gBRCAm patients and previous approvals in other tumor histologies have served as the scientific basis for the currently ongoing PARPi trials in prostate cancer [66,67].…”