PARP Inhibition in Patients with Advanced Urothelial Cancer - Expert Commentary

Treatment options for patients with urothelial cancer (UC) after first-line chemotherapy are limited. It is unclear if targeting DNA damage repair using Poly (ADP-ribose) polymerase (PARP) inhibitors will result in meaningful single-agent activity in this patient population.


A recently published study by Grivas et al. in BMC Cancer investigated the efficacy of rucaparib, a PARP inhibitor, in patients with advanced UC. A total of 97 patients were enrolled in the study. Most patients received prior platinum-based chemotherapy, and half of them received at least two prior lines for advanced disease. HRD-positivity was defined by somatic genome-wide loss of heterozygosity (LOH) ≥10%. Twenty patients (20.6%) had HRD-positive tumors, 30 (30.9%) HRD-negative tumors, and 47 (48.5%) with indeterminate HRD status.

A total of 95 patients had measurable disease. Unfortunately, no confirmed investigator-assessed objective responses were reported. Six patients had unconfirmed objective responses. Stable disease was reported in 22/95 (23.2%) patients. The duration of stable disease was not reported. There were no significant differences in response based on the HRD-status. The median progression-free survival was 1.8 months.

In patients with available tumor genomic analysis, 10/64 (15.6%) patients had alterations in a selected panel of 15 DNA damage repair (DDR) genes. Four patients had confirmed germline alterations in BRCA1 and CHEK2, but most patients did not have germline testing.

While this study did not meet its primary endpoint, this may reflect the unselected population and the current knowledge gaps in our understanding of the DDR alterations that determine response to PARP inhibition in patients with UC. Germline and somatic DDR mutations likely have different response profiles to PARP inhibition. Collectively considering DDR mutations as one category is challenging as individual variants in different genes are likely associated with heterogeneous responses to PARP inhibition. Addressing these knowledge gaps is critical for biomarker-selected precision medicine approaches testing PARP inhibitors in patients with advanced UC. This approach deserves consideration in light of the emerging evidence of the high prevalence of germline DDR mutations in patients with advanced UC.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York


References:

  1. Grivas P, Loriot Y, Morales-Barrera R, Teo MY, Zakharia Y, Feyerabend S, et al. Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS). BMC Cancer. 2021;21(1):1–13.
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