Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline <i>ATM</i> versus <i>BRCA2</i> mutations

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Among men with metastatic prostate cancer, about 10% have germline alterations in DNA damage response genes. Most studies have examined <jats:italic>BRCA2</jats:italic> alone or an aggregate of <jats:italic>BRCA1/2</jats:italic> and <jats:italic>ATM</jats:italic>. Emerging data suggest that <jats:italic>ATM</jats:italic> mutations may have distinct biology and warrant individual evaluation. The objective of this study is to determine whether response to prostate cancer systemic therapies differs between men with germline mutations in <jats:italic>ATM</jats:italic> (g<jats:italic>ATM)</jats:italic> and <jats:italic>BRCA2</jats:italic> (g<jats:italic>BRCA2)</jats:italic>.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>This is an international multicenter retrospective matched cohort study of men with prostate cancer harboring g<jats:italic>ATM</jats:italic> or g<jats:italic>BRCA2</jats:italic>. PSA<jats:sub>50</jats:sub> response (≥50% decline in prostate‐specific antigen) was compared using Fisher's exact test.</jats:p></jats:sec><jats:sec><jats:title>Results and Limitations</jats:title><jats:p>The study included 45 g<jats:italic>ATM</jats:italic> and 45 g<jats:italic>BRCA2</jats:italic> patients, matched on stage and year of germline testing. Patients with g<jats:italic>ATM</jats:italic> and g<jats:italic>BRCA2</jats:italic> had similar age, Gleason grade, and PSA at diagnosis. We did not observe differences in PSA<jats:sub>50</jats:sub> responses to abiraterone, enzalutamide, or docetaxel in metastatic castration resistant prostate cancer between the two groups; however, 0/7 with g<jats:italic>ATM</jats:italic> and 12/14 with g<jats:italic>BRCA2</jats:italic> achieved PSA<jats:sub>50</jats:sub> response to PARPi (<jats:italic>p</jats:italic> < .001). Median (95% confidence interval) overall survival from diagnosis to death was 10.9 years (9.5‐not reached) versus 9.9 years (7.1‐not reached, <jats:italic>p</jats:italic> = .07) for the g<jats:italic>ATM</jats:italic> and g<jats:italic>BRCA2</jats:italic> cohorts, respectively. Limitations include the retrospective design and lack of mutation zygosity data.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Conventional therapies can be effective in g<jats:italic>ATM</jats:italic> carriers and should be considered before PARPi, which shows limited efficacy in this group. Men with g<jats:italic>ATM</jats:italic> mutations warrant prioritization for novel treatment strategies.</jats:p></jats:sec>