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In patients with solid organ malignancies harboring germline or somatic alterations in DNA damage response (DDR), poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated therapeutic benefit. Such alterations have also been identified in patients with metastatic urothelial carcinoma; however, the efficacy of PARP inhibition in this particular population has not been clearly demonstrated.

In this single-arm, multi-institutional, , the investigators sought to evaluate the efficacy of olaparib in patients with metastatic urothelial cancer harboring somatic DDR alterations. Eligible patients had metastatic urothelial cancer that progressed after receiving prior platinum-based chemotherapy or were cisplatin-ineligible, and had identifiable somatic alterations in at least one of a prespecified list of DDR genes.

Participants received olaparib 300 mg twice daily and were evaluated for objective response rate as the primary study endpoint, which was defined as achieving either a complete or partial response based on pre-established criteria.

In the 19 patients enrolled, BRCA2 alterations were the most common somatic mutations (11 patients) identified. Patients received olaparib treatment for a median of 1.8 months, with four patients receiving treatment for less than 1 month due to either disease progression or adverse events. In the overall study group, an objective response was not observed in any patient, with a median progression-free survival and overall survival of 1.9 months and 9.5 months, respectively. Of note, prolonged stable disease (lasting > 6 months) was observed in only 26.3% of trial patients.

The investigators concluded that olaparib in patients with predominantly platinum-resistant metastatic urothelial cancer demonstrated negligible clinical activity. Despite the prevalence of DDR gene alterations in this patient population, this study determined that PARP inhibition does not provide therapeutic benefit, and thus, to date, has no role in the treatment paradigm of advanced urothelial cancer outside the context of further clinical trial investigations.

Muhannad Alsyouf, MD, is Assistant Professor of Urology at Loma Linda University and Riverside University Health System in Moreno Valley, in California.

Read the study here and an interview about it here.