Differential Response to Olaparib Treatment Among Men with Metastatic Castration-resistant Prostate Cancer Harboring BRCA1 or BRCA2 Versus ATM Mutations

Catherine H. Marshall, Alexandra O. Sokolova, Andrea L. McNatty, Heather H. Cheng, Mario A. Eisenberger, Alan H. Bryce, Michael T. Schweizer, Emmanuel S. Antonarakis

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

Background: Poly ADP-ribose polymerase (PARP) inhibitors, such as olaparib, are being explored as a treatment option for metastatic castration-resistant prostate cancer (mCRPC) in men harboring mutations in homologous recombination DNA-repair genes. Whether responses to PARP inhibitors differ according to the affected gene is currently unknown. Objective: To determine whether responses to PARP inhibitors differ between men with BRCA1/2 and those with ATM mutations. Design, setting, and participants: This was a multicenter retrospective review of 23 consecutive men with mCRPC and pathogenic germline and/or somatic BRCA1/2 or ATM mutations treated with olaparib at three academic sites in the USA. Outcome measurements and statistical analysis: The proportion of patients achieving a ≥50% decline in prostate-specific antigen (PSA50 response) was compared using Fisher's exact test. Clinical and radiographic progression-free survival (PFS) and overall survival were estimated using Kaplan-Meier analyses and compared using the log-rank test. Results and limitations: The study included two men with BRCA1 mutations, 15 with BRCA2 mutations, and six with ATM mutations. PSA50 responses to olaparib were achieved in 76% (13/17) of men with BRCA1/2 versus 0% (0/6) of men with ATM mutations (Fisher's exact test; p = 0.002). Patients with BRCA1/2 mutations had median PFS of 12.3 mo versus 2.4 mo for those with ATM mutations (hazard ratio 0.17, 95% confidence interval 0.05–0.57; p = 0.004). Limitations include the retrospective design and relatively small sample size. Conclusions: Men with mCRPC harboring ATM mutations experienced inferior outcomes to PARP inhibitor therapy compared to those harboring BRCA1/2 mutations. Alternative therapies should be explored for patients with ATM mutations. Patient summary: Mutations in BRCA1/2 and ATM genes are common in metastatic prostate cancer. In this study we compared outcomes for men with BRCA1/2 mutations to those for men with ATM mutations being treated with olaparib. We found that men with ATM mutations do not respond as well as men with BRCA1/2 mutations.

Original languageEnglish (US)
Pages (from-to)452-458
Number of pages7
JournalEuropean Urology
Volume76
Issue number4
DOIs
StatePublished - Oct 2019
Externally publishedYes

Bibliographical note

Funding Information:
Funding/Support and role of the sponsor: This work was partly supported by National Institutes of Health Cancer Center Support Grants P30 CA006973 and P30 CA015704, Pacific Northwest Prostate Cancer SPORE CA097186, Department of Defense grant W81XWH-16-PCRP-CCRSA, the Patrick C. Walsh Research Fund, and Institute for Prostate Cancer Research and Prostate Cancer Foundation Awards. The sponsors played no direct role in the study.

Funding Information:
Funding/Support and role of the sponsor: This work was partly supported by National Institutes of Health Cancer Center Support Grants P30 CA006973 and P30 CA015704 , Pacific Northwest Prostate Cancer SPORE CA097186 , Department of Defense grant W81XWH-16-PCRP-CCRSA , the Patrick C. Walsh Research Fund , and Institute for Prostate Cancer Research and Prostate Cancer Foundation Awards . The sponsors played no direct role in the study.

Funding Information:
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, AstraZeneca, Clovis, and Merck; has received institutional research funding from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Bristol Myers-Squibb, AstraZeneca, Clovis, and Merck; and is co-inventor of a biomarker technology that has been licensed to Qiagen. Heather H. Cheng has received institutional research funding from Celgene, Clovis, Inovio, Janssen, Medivation, and Sanofi. Michael T. Schweizer is a paid consultant/advisor to Janssen and has received institutional research funding from Janssen, AstraZeneca, Hoffmann La Roche, Zenith Epigenetics, and Pfizer. Catherine H. Marshall has received research funding via the Conquer Cancer Foundation from Bristol Myers-Squibb and travel support from Dava Oncology, and is a paid consultant to the McGraw-Hill publishing company. The remaining authors have nothing to disclose.

Publisher Copyright:
© 2019 European Association of Urology

Keywords

  • ATM
  • BRCA2
  • Olaparib
  • PARP inhibitor
  • Prostate cancer

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