Parp inhibitors in prostate cancer: Practical guidance for busy clinicians

The management of prostate cancer entered a new era of biomarker-driven therapy in May of 2020, when the US Food and Drug Administration (FDA) approved the poly(ADP-ribose) poly-merase (PARP) inhibitors rucaparib and olaparib as the first targeted therapies in biomarker-preselected patients with metastatic castra-tion-resistant prostate cancer. This approval provided new options for patients with deleterious BRCA1 or BRCA2 mutations (olaparib and rucaparib), or with deleterious mutations in one of a number of homologous recombination repair genes (olaparib). Compared with either enzalutamide or abiraterone, olaparib demonstrated an overall survival benefit in men with metastatic castration-resis-tant prostate cancer who had disease progression while receiving enzalutamide and/or abiraterone. Additional PARP inhibitors are currently being evaluated as monotherapy. The data are strongest for alterations in BRCA2; alterations in other genes are associated with less benefit or occur less frequently. To date, tissue DNA remains the gold standard for identifying predictive mutations, but sequencing from tissue DNA fails to provide a result in approxi-mately 30% of cases. Biopsies of metastatic sites are more likely to yield results and more likely to identify predictive alterations. Plasma-based sequencing platforms are also approved by the FDA, and they appear to provide a result in most patients with late-stage disease. The best way and time to evaluate for the presence of selection biomarkers are not firmly established, but patients whose disease has progressed on androgen deprivation therapy should be evaluated. PARP inhibitors are also being studied in combination with other therapies, such as AR-targeted therapies, immunothera-pies, and radiation, among others, in unselected patients.