Genomic integrity and cell survival depend on the high-fidelity repair of DNA damage repair (DDR) [either single-strand- (SSBs) or double-strand breaks (DSBs)]. Genito-urinary malignancies that either repair DSBs through the homologous recombination repair (HRR) system (BRCA1/2 pathway) or SSBs through the Poly-ADP-ribose polymerase (PARP) pathway frequently have DDR abnormalities. Through synthetic lethality, PARP inhibitors (PARPi) take advantage of flaws in the DNA repair pathway, with DSBs being repaired only in HR-proficient cells but not in HR-deficient (HRD) cells.
There was mounting evidence that patients with genito-urinary malignancies should be tested for germinal and somatic DDR changes. Precision medicine was possible because of PARPi, which has previously demonstrated considerable survival advantages in patients with HRR mutations in high-tech settings. Despite developing early in prostate cancer (PCa) development and mostly affecting BRCA2, ATM, CHEK2, and BRCA1, somatic mutations in the HRR pathway are seen in up to 27% of metastatic resistant-to-castration PCa (mCRPC) in advanced PCa.
In general, 30 to 50% of instances of HRR changes included germinal alterations, and carriers of germinal BRCA2-alterations had a 4.65-fold greater relative risk of developing PCa than non-carriers. Because it may be a possible indicator of response to first-line therapy [androgen-receptor signaling inhibitors (ARSI) vs. taxane-base chemotherapy] and permits determining eligibility for PARPi usage, determining the DDR gene status is advised in metastatic patients, a fortiori in mCRPC settings.
Thus, following the approval of new hormonal treatment (NHT) for patients with a change in 14 of 15 prespecified HRR genes, olaparib (in combination with androgen deprivation therapy) enhanced overall survival in mCRPC HRD patients. Additionally, the use of either olaparib or niraparib has been suggested in conjunction with NHT, with a radiographic progression-free survival enhancement when combined with abiraterone, as pre-clinical studies revealed synergic effect between PARPi and ARSI. With a clear correlation between DDR gene mutation and increased tumor mutation burden and susceptibility to cisplatin-based chemotherapy and immunotherapy, a DDR gene mutation is found in 23-54% of patients with urothelial carcinoma, most commonly in muscle-invasive bladder cancer. Recent phase 2 studies supported the selection of patients for PARPi therapy in advanced urothelial cancer on the basis of HRR status. In addition, detrimental somatic changes have been documented as recurring genomic events in patients with advanced renal cell carcinomas (RCC), while pathogenic germline variations in DDR genes have been found in 7.3% of instances of RCC.