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).
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.
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.
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.
European journal of cancer (Oxford, England : 1990). 2020 Jul 04 [Epub ahead of print]
Maarten J van der Doelen, Pedro Isaacsson Velho, Peter H J Slootbeek, Samhita Pamidimarri Naga, Maren Bormann, Sjoerd van Helvert, Leonie I Kroeze, Inge M van Oort, Winald R Gerritsen, Emmanuel S Antonarakis, Niven Mehra
Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Urology, Radboud University Medical Center, Nijmegen, the Netherlands., Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Medical Oncology, Hospital Moinhos de Vento, Porto Alegre, Brazil., Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands., Department of Tumor Immunology, Radboud University Medical Center, Nijmegen, the Netherlands., Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands., Department of Urology, Radboud University Medical Center, Nijmegen, the Netherlands., Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address: .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/32634759