TY - JOUR
T1 - Impact of DNA damage repair defects on response to radium-223 and overall survival in metastatic castration-resistant prostate cancer
AU - van der Doelen, Maarten J.
AU - Isaacsson Velho, Pedro
AU - Slootbeek, Peter H.J.
AU - Pamidimarri Naga, Samhita
AU - Bormann, Maren
AU - van Helvert, Sjoerd
AU - Kroeze, Leonie I.
AU - van Oort, Inge M.
AU - Gerritsen, Winald R.
AU - Antonarakis, Emmanuel S.
AU - Mehra, Niven
N1 - Publisher Copyright:
© 2020 The Author(s)
PY - 2020/9
Y1 - 2020/9
N2 - 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 tumour 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 versus 17.0 months; HR 2.29; P = 0.01). Median TAP and TST in the DDR+ and DDR− patients was 6.9 versus5.8 months (HR = 1.48; P = 0.15), and 8.9 versus7.3 months (HR = 1.58; P = 0.08), respectively. DDR+ patients more frequently completed radium-223 therapy (79% versus 47%; P = 0.05). No difference in biochemical responses were seen. Conclusion: Patients harbouring DDR aberrations showed significant OS benefit, and more commonly completed radium-223 therapy. These findings need prospective confirmation and support strategies of genotoxic agents such as radium-223 in patients harbouring DDR defects.
AB - 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 tumour 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 versus 17.0 months; HR 2.29; P = 0.01). Median TAP and TST in the DDR+ and DDR− patients was 6.9 versus5.8 months (HR = 1.48; P = 0.15), and 8.9 versus7.3 months (HR = 1.58; P = 0.08), respectively. DDR+ patients more frequently completed radium-223 therapy (79% versus 47%; P = 0.05). No difference in biochemical responses were seen. Conclusion: Patients harbouring DDR aberrations showed significant OS benefit, and more commonly completed radium-223 therapy. These findings need prospective confirmation and support strategies of genotoxic agents such as radium-223 in patients harbouring DDR defects.
KW - DNA repair
KW - Homologous recombination
KW - Metastatic castration-resistant prostate cancer
KW - Mutation
KW - Next-generation sequencing
KW - Radium-223
UR - http://www.scopus.com/inward/record.url?scp=85087357171&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85087357171&partnerID=8YFLogxK
U2 - 10.1016/j.ejca.2020.05.001
DO - 10.1016/j.ejca.2020.05.001
M3 - Article
C2 - 32634759
AN - SCOPUS:85087357171
SN - 0959-8049
VL - 136
SP - 16
EP - 24
JO - European Journal of Cancer
JF - European Journal of Cancer
ER -