Impact of DNA damage repair defects on response to radium-223 and overall survival in metastatic castration-resistant prostate cancer

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

doi:10.1016/j.ejca.2020.05.001

Maarten J Van Der Doelen, Pedro Isaacsson Velho + Show 9 more

Open Access

https://doi.org/10.1016/j.ejca.2020.05.001

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Abstract

PurposeRadium-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 methodsIncluded 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. ResultsNinety-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. ConclusionPatients 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.

Highlights

Prostate cancer is the cancer with the highest incidence and the second leading cancer-related cause of death in men worldwide [1]
DNA damage repair (DDR) genes play a crucial role in protecting the genomic integrity, through detection of DNA damage, signalling to cell-cycle checkpoints, and DNA repair [4]
We show that patients with pathogenic DDR alterations, including BRCA1 and BRCA2, and additional genes with indirect involvement in homologous recombination, appear to benefit from radium-223 therapy

Summary

Introduction

Prostate cancer is the cancer with the highest incidence and the second leading cancer-related cause of death in men worldwide [1]. Since 2004, several new lifeprolonging systemic therapies have been registered for treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). The inability to repair DNA damage by NHEJ or other mechanisms can lead to accumulation of deletions and mutations [5]. Germline mutations in selected DDR genes result in an increased incidence of prostate cancer but are associated to a more aggressive disease course [6,7]. Genomic aberrations that impair DNA repair occur at a frequency of 20e25% in advanced prostate cancer [8]. Mutations in homologous recombination genes, such as BRCA1, BRCA2, PALB2 or other genes constituting the DNA damage machinery, such as ATM, ATR, or CHEK2, are candidate predictive biomarkers for targeted therapies like poly-ADP ribose polymerase (PARP) inhibitors

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