Velho PI, et al. - Through a retrospective single-institution stud of 190 metastatic castrate-resistant prostate cancer (mCRPC) subjects for whom germline and/or somatic DNA sequencing data were available, the researchers assessed the potential influence of germline or somatic HR-deficiency (HRD) mutations on radium-223 (a bone-seeking α-emitter that induces double-strand DNA breaks, thereby killing cancer cells in the bone microenvironment) efficiency in mCRPC with bone metastasis. Out of 190, 28 received standard-of-care radium-223 at Johns Hopkins between February 2013 and February 2018, out of which 10 men had a germline/somatic HRD mutation and 18 men did not. Men with HRD mutations (HRD+) had numerically lower ages, more soft-tissue metastases, and greater baseline ALP levels. HRD(+) patients exhibited greater alkaline phosphatase (ALP) responses more prolonged time to ALP progression and a trend toward longer overall survival, in comparison with HRD(–) men. Among the two groups, prostate-specific antigen responses and time to next systemic therapy were similar. Hence, bone-metastatic CRPC subjects with inactivating HRD mutations exhibited markedly enhanced ALP responses and time to ALP progression. Moreover, among HRD mutations and radium-223 activity, these results should prompt prospective validation of the “synthetic lethality” hypothesis.