DDR Mutations Not Linked to Clinical Benefit of Olaparib in mUC

By Emily Menendez - Last Updated: September 11, 2023

Poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors may offer a therapeutic benefit in patients with metastatic urothelial cancer (mUC). PARP inhibitors are the first approved targeted agent to manage DNA damage response (DDR) genes and have demonstrated a clinical benefit in patients with solid tumors who carry germline or somatic alterations in those genes.

As somatic alterations in DDR genes are common in patients with advanced urothelial cancer, researchers examined the use of the PARP inhibitor olaparib to determine the drug’s potential therapeutic benefit in patients with mUC with somatic DDR alterations.

The phase 2 study included 19 patients with mUC who harbored somatic DDR alterations. Nine patients (47.4%) had received prior cisplatin-based chemotherapy, 10 patients (52.6%) had alterations in homologous recombination (HR) genes, 8 patients (42.1%) had pathogenic BRCA2 mutations, and 2 patients had alterations in other HR genes. The median patient age was 66 years (range, 45-82 years).

Patients were administered olaparib 300 mg twice daily, with a primary end point of objective response rate. Secondary end points were safety, progression-free survival (PFS), and overall survival (OS).

The trial ended early before slow accrual; no patients achieved a partial response, but 6 patients achieved stable disease lasting 2.13 to 16.10 months. The median PFS was 1.9 months (range, 0.8-16.1 months), and the median OS was 9.5 months (range, 1.5-22.1 months).

In patients with mUC and DDR alterations, olaparib demonstrated limited antitumor activity. This outcome may be due to poorly characterized functional implications of certain DDR alterations, or to cross-resistance with platinum-based chemotherapy.