DDR Alterations Signal Immunotherapy Benefit in Urothelial Carcinoma

Alterations to DNA damage response and repair (DDR) genes were associated with improved response rates and other outcomes in patients with metastatic urothelial carcinoma who were treated with nivolumab or atezolizumab, according to a new study.

“The recent approval of immune checkpoint inhibitors that target the PD-1/PD-L1 axis… has revolutionized the management of metastatic urothelial carcinoma,” wrote study authors including Jonathan E. Rosenberg, MD, of Memorial Sloan Kettering Cancer Center in New York. “The identification of clinically useful biomarkers that identify patients most likely to benefit from immune checkpoint blockade remains an ongoing challenge.”

Alterations in DDR genes have been associated with enhanced responsiveness to platinum-based chemotherapy. In the new analysis, the investigators examined whether the presence of DDR mutations might be associated with similar benefit in the immunotherapy setting.

They included a total of 60 patients enrolled in prospective clinical trials who were treated with nivolumab or atezolizumab. Of those, 15 patients had deleterious DDR alterations, 13 had other DDR alterations, and 32 were DDR wild-type; the most commonly altered genes included ATM (7 patients); POLE (3 patients); and BRCA2, ERCC2, FANCA, and MSH6 (2 patients each). Most of the cohort was male (88.3%), and the median age was 67.0 years, and this did not differ between the wild-type or mutated patients. The results of the analysis were published in the Journal of Clinical Oncology.

Patients with deleterious DDR alterations had better ECOG performance status (P = .001), and had a lower incidence of hepatic involvement (P = .011).

In the full cohort, objective responses to immunotherapy were observed in 41.7% of patients. Patients with DDR alterations had a response rate of 67.9%, compared with 18.8% of wild-type patients (P < .001). Patients with a known or likely deleterious DDR mutation had an objective response rate of 80%, compared with 53.9% in those with DDR alterations of unknown significance, and 18.8% in the wild-type group.

On a multivariate analysis, the presence of any DDR alteration yielded an odds ratio (OR) for response of 5.79 compared with wild-type patients (95% CI, 1.26–26.58; P = .024). For deleterious DDR alterations compared with wild-type patients, the multivariate OR was 19.02 (95% CI, 3.65–99.17; P < .001).

The median overall survival was not yet reached in patients with deleterious DDR alterations, and 71.5% were alive at 12 months. Patients with no DDR alterations had a median overall survival of 9.3 months. Deleterious mutations yielded a hazard ratio for mortality of 0.27 (95% CI, 0.10–0.73; P = .001), compared with wild-type patients.

“This study shows that patients with DDR gene alterations are more likely to experience objective responses, longer progression-free survival, and improved overall survival than patients with wild-type DDR genes,” the authors concluded. “Whether the association is predictive or prognostic should be investigated further in larger data sets from randomized studies.”