Efficacy of Radium-223 in Bone-metastatic Castration-resistant Prostate Cancer with and Without Homologous Repair Gene Defects

Pedro Isaacsson Velho, Fahad Qazi, Sayeedul Hassan, Michael A. Carducci, Samuel R. Denmeade, Mark C. Markowski, Daniel L. Thorek, Theodore L. DeWeese, Daniel Y. Song, Phuoc T. Tran, Mario A. Eisenberger, Emmanuel S. Antonarakis

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Background: Pathogenic mutations in genes mediating homologous recombination (HR) DNA repair are present in 20–30% of men with metastatic castrate-resistant prostate cancer (mCRPC). Radium-223 is a bone-seeking α-emitter that induces double-strand DNA breaks, thereby killing cancer cells in the bone microenvironment. Objective: To evaluate the potential impact of germline or somatic HR-deficiency (HRD) mutations on radium-223 efficacy in mCRPC with bone metastasis. Design, setting, and participants: This is a retrospective single-institution study. Medical records of 190 mCRPC patients for whom germline and/or somatic DNA sequencing data were available were reviewed. Of these patients, 28 had received standard-of-care radium-223 at Johns Hopkins between February 2013 and February 2018. Outcome measurements and statistical analysis: Alkaline phosphatase (ALP) responses and time-to-ALP-progression were the coprimary endpoints. Prostate-specific antigen (PSA) responses, overall survival (OS), and time to next systemic therapy were also evaluated. Results and limitations: Of the 28 patients included, 10 men (35.7%) had a germline/somatic HRD mutation (three in BRCA2, and one each in ATM, ATR, CHEK2, FANCG, FANCI, FANCL, and PALB2) and 18 (64.3%) did not. Men with HRD mutations (HRD +) had numerically lower ages (66 vs 73 yr, p = 0.25), more soft-tissue metastases (50% vs 38%, p = 0.43), and higher baseline ALP levels (130 vs 108 U/l, p = 0.84). Compared with HRD(–) men, HRD(+) patients showed greater ALP responses (80% vs 39%, p = 0.04), longer time to ALP progression (median10.4 vs 5.8 mo, hazard ratio [HR] 6.4, p = 0.005), and a trend toward longer OS (median 36.9 vs 19.0 mo, HR 3.3, p = 0.11). PSA responses (0% vs 0%, p > 0.99) and time to next systemic therapy (HR 1.5, p = 0.39) were similar between the two groups. Results are limited by the retrospective nature of the analysis and the small sample size. Conclusions: In this exploratory study, bone-metastatic CRPC patients with inactivating HRD mutations demonstrated significantly improved ALP responses and time to ALP progression. These results should motivate prospective validation of the “synthetic lethality” hypothesis between HRD mutations and radium-223 activity. Patient summary: In this report, we retrospectively examined outcomes to metastatic prostate cancer in patients with and without DNA repair mutations who received radium-223, a therapy that kills cancer cells by causing direct DNA damage. Our study suggested that patients who have inherited or acquired DNA repair gene mutations derived greater benefit from radium-223 when compared with patients without these mutations. We concluded that radium-223 might have an important role in this setting; however, prospective studies are needed to confirm whether DNA repair mutations truly make radium-223 work better or not.

Original languageEnglish (US)
Pages (from-to)170-176
Number of pages7
JournalEuropean Urology
Volume76
Issue number2
DOIs
StatePublished - Aug 2019
Externally publishedYes

Bibliographical note

Funding Information:
Our preliminary findings suggest that bone-predominant mCRPC patients with germline and/or somatic mutations in HR-pathway genes may be associated with clinical benefit from radium-223 (in terms of ALP responses, normalization of ALP, and the time to ALP progression) as well as potential prolongation of survival. The retrospective nature of our study and the limitations inherent to that design suggest that these provocative findings should be considered as hypothesis generating only at this time, but may spark dedicated trials investigating radium-223 in HR-deficient mCRPC patients. Author contributions : Emmanuel S. Antonarakis had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design : Isaacsson Velho, Antonarakis. Acquisition of data : Isaacsson Velho, Qazi, Hassan. Analysis and interpretation of data : Isaacsson Velho, Antonarakis. Drafting of the manuscript : Isaacsson Velho, Antonarakis. Critical revision of the manuscript for important intellectual content : Isaacsson Velho, Qazi, Hassan, Carducci, Denmeade, Markowski, Thorek, DeWeese, Song, Tran, Eisenberger, Antonarakis. Statistical analysis : Isaacsson Velho. Obtaining funding : Antonarakis. Administrative, technical, or material support : Qazi, Hassan, Carducci, Denmeade, Markowski, Thorek, DeWeese, Song, Tran, Eisenberger, Antonarakis. Supervision : Isaacsson Velho, Qazi, Hassan, Carducci, Denmeade, Markowski, Thorek, DeWeese, Song, Tran, Eisenberger, Antonarakis. Other : None. Financial disclosures: Emmanuel S. Antonarakis certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Emmanuel S. Antonarakis is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Medivation, ESSA, AstraZeneca, Clovis, and Merck; he has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Bristol Myers-Squibb, AstraZeneca, Clovis, and Merck; and he is the coinventor of a biomarker technology that has been licensed to Tokai and Qiagen. The remaining authors report no relevant conflicts of interest. Funding/Support and role of the sponsor : This work was partially supported by National Institutes of Health Grant P30 CA006973 (E.S.A.) and Department of Defense grant W81XWH-16-PCRP-CCRSA (E.S.A.). Appendix A

Publisher Copyright:
© 2018 European Association of Urology

Keywords

  • Cancer
  • DNA repair
  • Germline
  • Mutations
  • Prostate cancer
  • Radium-223
  • Somatic

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