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 journalArticle

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 (PSA 50 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. PSA 50 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. In this retrospective review of 23 patients with BRCA1/2 or ATM mutations treated with olaparib, we found that none of six men with ATM mutations achieved a 50% decline in prostate-specific antigen, compared to 13/17 men with BRCA1/2 mutations. Patients with BRCA1/2 mutations also had longer progression-free survival on olaparib treatment. Men with metastatic castration-resistant prostate cancer harboring ATM mutations may not respond to PARP inhibitors as well as men with BRCA1/2 mutations and may require alternative therapies.

Original languageEnglish (US)
JournalEuropean Urology
DOIs
StatePublished - Jan 1 2019

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Castration
Prostatic Neoplasms
Mutation
Therapeutics
olaparib
Disease-Free Survival
Prostate-Specific Antigen
Complementary Therapies
Genes
Recombinational DNA Repair

Keywords

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

ASJC Scopus subject areas

  • Urology

Cite this

Differential Response to Olaparib Treatment Among Men with Metastatic Castration-resistant Prostate Cancer Harboring BRCA1 or BRCA2 Versus ATM Mutations. / Marshall, Catherine H.; Sokolova, Alexandra O.; McNatty, Andrea L.; Cheng, Heather H.; Eisenberger, Mario A.; Bryce, Alan H.; Schweizer, Michael T.; Antonarakis, Emmanuel S.

In: European Urology, 01.01.2019.

Research output: Contribution to journalArticle

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title = "Differential Response to Olaparib Treatment Among Men with Metastatic Castration-resistant Prostate Cancer Harboring BRCA1 or BRCA2 Versus ATM Mutations",
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 (PSA 50 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. PSA 50 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. In this retrospective review of 23 patients with BRCA1/2 or ATM mutations treated with olaparib, we found that none of six men with ATM mutations achieved a 50{\%} decline in prostate-specific antigen, compared to 13/17 men with BRCA1/2 mutations. Patients with BRCA1/2 mutations also had longer progression-free survival on olaparib treatment. Men with metastatic castration-resistant prostate cancer harboring ATM mutations may not respond to PARP inhibitors as well as men with BRCA1/2 mutations and may require alternative therapies.",
keywords = "ATM, BRCA2, Olaparib, PARP inhibitor, Prostate cancer",
author = "Marshall, {Catherine H.} and Sokolova, {Alexandra O.} and McNatty, {Andrea L.} and Cheng, {Heather H.} and Eisenberger, {Mario A.} and Bryce, {Alan H.} and Schweizer, {Michael T.} and Antonarakis, {Emmanuel S.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.eururo.2019.02.002",
language = "English (US)",
journal = "European Urology",
issn = "0302-2838",
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TY - JOUR

T1 - Differential Response to Olaparib Treatment Among Men with Metastatic Castration-resistant Prostate Cancer Harboring BRCA1 or BRCA2 Versus ATM Mutations

AU - Marshall, Catherine H.

AU - Sokolova, Alexandra O.

AU - McNatty, Andrea L.

AU - Cheng, Heather H.

AU - Eisenberger, Mario A.

AU - Bryce, Alan H.

AU - Schweizer, Michael T.

AU - Antonarakis, Emmanuel S.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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 (PSA 50 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. PSA 50 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. In this retrospective review of 23 patients with BRCA1/2 or ATM mutations treated with olaparib, we found that none of six men with ATM mutations achieved a 50% decline in prostate-specific antigen, compared to 13/17 men with BRCA1/2 mutations. Patients with BRCA1/2 mutations also had longer progression-free survival on olaparib treatment. Men with metastatic castration-resistant prostate cancer harboring ATM mutations may not respond to PARP inhibitors as well as men with BRCA1/2 mutations and may require alternative therapies.

AB - 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 (PSA 50 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. PSA 50 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. In this retrospective review of 23 patients with BRCA1/2 or ATM mutations treated with olaparib, we found that none of six men with ATM mutations achieved a 50% decline in prostate-specific antigen, compared to 13/17 men with BRCA1/2 mutations. Patients with BRCA1/2 mutations also had longer progression-free survival on olaparib treatment. Men with metastatic castration-resistant prostate cancer harboring ATM mutations may not respond to PARP inhibitors as well as men with BRCA1/2 mutations and may require alternative therapies.

KW - ATM

KW - BRCA2

KW - Olaparib

KW - PARP inhibitor

KW - Prostate cancer

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