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

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish (US)
Pages (from-to)16-24
Number of pages9
JournalEuropean Journal of Cancer
Volume136
DOIs
StatePublished - Sep 2020
Externally publishedYes

Bibliographical note

Funding Information:
Tumour samples of all patients were previously sequenced by non-profit institutes (Center for Personalized Cancer Treatment), by fee for service providers (Foundation Medicine [FoundationOne], Personal Genome Diagnostics, Color Genomics, Invitae) and/or by a custom in-house NGS panel using single-molecule molecular inversion probe?based sequencing [13].This research was funded by Bayer, The Netherlands. The funding organisation had no role in the design and conduct of the study, the collection, management, analysis and interpretation of the data, and writing of the report.M.J.v.d.D. discloses grants from Bayer, grants from Janssen-Cilag and personal fees from Astellas.I.M.v.O. reports grants and personal fees from Astellas, grants and personal fees from Bayer, grants and personal fees from Janssen-Cilag and grants and personal fees from Sanofi.W.R.G. reports personal fees from Bayer and MSD and reports grants from Astellas, Bayer and Janssen-Cilag.E.S.A. reports grants and personal fees from Janssen, personal fees from Astellas, grants and personal fees from Sanofi-Genzyme, grants and personal fees from Dendreon, Seal Beach, California, USA, personal fees from Pfizer, grants and personal fees from AstraZeneca, grants and personal fees from Clovis Oncology, Boulder, Colorado, USA, grants and personal fees from Merck, grants from Johnson & Johnson, grants from Genentech, San Francisco, California, USA, grants from Novartis, grants from Bristol Myers Squibb and personal fees from Amgen. In addition E.S.A. reports a patent PCT/US2015/046,806; US20170275673A1 on an AR-V7 biomarker technology licenced to Qiagen. E.S.A. reports partial fund by NIH Cancer Center Support Grant P30 CA006973.N.M. reports personal fees from Bayer, grants and personal fees from Jansen-Cilag, personal fees from MSD, grants and personal fees from Roche, grants and personal fees from Astellas grants and personal fees from Sanofi.

Funding Information:
W.R.G. reports personal fees from Bayer and MSD and reports grants from Astellas , Bayer and Janssen-Cilag .

Funding Information:
E.S.A. reports grants and personal fees from Janssen, personal fees from Astellas , grants and personal fees from Sanofi- Genzyme , grants and personal fees from Dendreon, Seal Beach, California, USA, personal fees from Pfizer , grants and personal fees from AstraZeneca , grants and personal fees from Clovis Oncology, Boulder, Colorado, USA, grants and personal fees from Merck , grants from Johnson & Johnson , grants from Genentech, San Francisco, California, USA , grants from Novartis , grants from Bristol Myers Squibb and personal fees from Amgen . In addition E.S.A. reports a patent PCT/US2015/046,806; US20170275673A1 on an AR-V7 biomarker technology licenced to Qiagen. E.S.A. reports partial fund by NIH Cancer Center Support Grant P30 CA006973.

Publisher Copyright:
© 2020 The Author(s)

Keywords

  • DNA repair
  • Homologous recombination
  • Metastatic castration-resistant prostate cancer
  • Mutation
  • Next-generation sequencing
  • Radium-223

PubMed: MeSH publication types

  • Journal Article
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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