PARP Inhibitors in Genitourinary Cancer: A New Paradigm Beyond Prostate Cancer.

Abstract

Alterations in the homologous recombination repair genes, such as BRCA1 and BRCA2, are prevalent in various cancers, presenting a unique opportunity to develop synthetic lethal strategies that target homologous recombination deficiency (HRD). Poly ADP-ribose polymerase inhibitors (PARPis) have been developed to induce synthetic lethality in tumors with HRD by inhibiting the repair of single-strand DNA breaks. Beyond the initial approach to target cancers associated with HRD, the utility of PARPis has expanded to combination therapy with immune checkpoint inhibitors, anti-angiogenic drugs, or anti-androgen drugs based on the molecular biological rationale. In the field of genitourinary (GU) cancer, PARPis, such as olaparib, rucaparib, and talazoparib, are approved by the Food and Drug Administration in metastatic prostate cancer patients with BRCA1/2 mutations, sometimes in combination with other agents (e.g., olaparib plus abiraterone acetate, or talazoparib plus enzalutamide). More recently, pivotal clinical trials have broadened the potential of PARPis to the other GU cancers, including urothelial carcinoma and renal cell carcinoma. In this review, we examine the biomarkers for the response to PARPis beyond mutations in BRCA1/2 and discuss the current state and future perspectives of PARPis in GU cancers.