Maarten van der Doelen

Chapter 7

ABSTRACT Purpose

Radium-223 is a targeted alpha radiation therapy for metastatic castration-resistant prostate cancer. DNA damage repair (DDR) defective prostate cancers, specifically genetic aberrations leading to homologous recombination deficiency (HRD), accumulate irreparable DNA damage following genotoxic treatment. This retrospective study assessed DDR mutation status in patients treated with radium-223, investigating their association with efficacy and overall survival (OS). Patients and methods Included patients were treated with radium-223 and had results from primary or metastatic tumor tissue of a comprehensive next-generation sequencing panel of DDR genes, including canonical HRD genes. Patients were grouped by presence (DDR+) or absence (DDR-) of pathogenic somatic or germline aberrations in DDR genes. We evaluated OS, time to ALP progression (TAP), time to initiation of subsequent systemic therapy (TST) and biochemical responses between DDR groups. Results Ninety-three patients were included. Twenty-eight (30%) patients had DDR mutations, most frequently in ATM (8.6%), BRCA2 (7.5%), and CDK12 (4.3%) genes. DDR+ patients showed prolonged OS (median 36.3 vs. 17.0 months; HR 2.29; P = 0.01). Median TAP and TST in the DDR+ and DDR- patients was 6.9 vs. 5.8 months (HR 1.48; P = 0.15), and 8.9 vs. 7.3 months (HR 1.58; P = 0.08), respectively. DDR+ patients more frequently completed radium-223 therapy (79% vs 47%; P = 0.05). No difference in biochemical responses were seen. Conclusion Patients harboring DDR aberrations showed significant OS benefit, andmore commonly completed radium-223 therapy. These findings need prospective confirmation, and support strategies of genotoxic agents such as radium-223 in patients harboring DDR defects.

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