Posted: Tuesday, September 5, 2023
Reducing the activity of PARP inhibition in patients with urothelial carcinoma may have clinical benefits in the future, although the approach needs refinement. That was the perspective of Abhishek Tripathi, MD, of City of Hope Comprehensive Cancer Center, Duarte, California, and Seth P. Lerner, MD, of Baylor College of Medicine, Houston, who shared their assessment of the emerging role of PARP inhibitors in this patient population in an editorial published in JCO Precision Oncology.
“PARP, specifically PARP-1, plays a crucial role in DNA damage repair,” they stated. “Pharmacologic inhibition of PARP-1 leads to formation of DNA-protein crosslinks, which trigger collapse of replication forks, accumulation of double-strand breaks, and tumor cell death.”
The editorial addressed a recent phase II study that attempted to use PARP inhibitors as monotherapy in urothelial carcinoma. The patient cohort was heavily pretreated, and the best result from the study was stable disease lasting for 16 months. Dr. Tripathi and Dr. Lerner noted that the authors from the primary study “should be congratulated for one of the first published biomarker-selected multicenter trials of PARP inhibitor monotherapy in advanced urothelial carcinoma.” The results of the study provided a call for a multi-institution and investigator-initiated study in which the patient profile could be better controlled.
To improve the use of PARP inhibitors, the authors addressed a number of factors. One difficulty is the identification of suitable patients. This can be achieved through next-generation sequencing, they proposed. Another factor is prior treatment. It’s suggested that platinum-based therapies, which are often used in patients with advanced urothelial carcinomas, could affect the efficacy of PARP inhibitors. Finally, the use of synergistic treatment may prove to be of benefit, in combination with PARP inhibitors. It is common to see upregulated PD-L1 expression with DNA damage repair mutations, Dr. Tripathi and Dr. Lerner noted, so combining both PD-1 and PARP inhibition may improve outcomes in this patient population.
Disclosure: For full disclosures of the study authors, visit ascopubs.org.