DNA Repair Gene Alterations and PARP Inhibitor Response in Patients With Metastatic Castration-Resistant Prostate Cancer

Authors:
Eric Lu Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

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George V. Thomas Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

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Yiyi Chen Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

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Alexander W. Wyatt Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

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Paul Lloyd Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

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Jack Youngren Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

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David Quigley Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

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Raymond Bergan Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

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Shawna Bailey Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

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Tomasz M. Beer Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

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Felix Y. Feng Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

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Eric J. Small Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

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Joshi J. Alumkal Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

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Volume/Issue:
Volume 16: Issue 8
Online Publication Date:
Aug 2018
DOI:
https://doi.org/10.6004/jnccn.2018.7020
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Background: PARP inhibition is a promising therapeutic strategy for the treatment of men with metastatic castration-resistant prostate cancer whose tumors harbor homologous recombination DNA repair gene alterations. However, questions remain for many practicing clinicians about which patients are ideally suited for PARP inhibitor treatment. This report details our institutional experience using PARP inhibitor therapy in patients whose tumors harbored specific DNA repair gene alterations. Patients and Methods: We performed a retrospective chart review to identify patients at Oregon Health & Science University who were treated with PARP inhibition. We identified 8 patients and determined the impact of the specific DNA repair gene alterations on tumor response and time on treatment with PARP inhibition. Results: A number of DNA repair gene alterations were identified. Three patients had pathogenic BRCA2 mutations and one had a BRCA2 mutation of uncertain significance. Conversely, the 4 other patients' tumors harbored alterations in other DNA repair genes, none of which were clearly pathogenic. A statistically significant difference in benefit was seen between patients whose tumors harbored BRCA2 gene alterations and those whose tumors did not, as measured by >50% decline in prostate-specific antigen levels (100% vs 0%; P=.03) and duration on therapy (31.4 vs 6.4 weeks; P=.03). Conclusions: Our results demonstrate that not all DNA repair alterations are equally predictive of PARP inhibitor response. Importantly, all responding patients had tumors harboring BRCA2 DNA repair alterations, including one without a known pathogenic mutation. Conversely, among the 4 nonresponders, several DNA repair alterations in genes other than BRCA2 were identified that were not clearly pathogenic. This demonstrates the need to carefully examine the functional relevance of the DNA repair alterations identified, especially in genes other than BRCA2, when considering patients for PARP inhibitor treatment.

Correspondence: Joshi J. Alumkal, MD, Department of Medicine, Oregon Health & Science University, 3303 SW Bond Avenue, CH14R, Portland, OR 97239. Email: alumkalj@ohsu.edu

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Copyright:
Copyright © 2018 by the National Comprehensive Cancer Network 2018
Page Numbers:
5
Article Category:
Research Article
Received:
15 Nov 2017
Accepted:
27 Feb 2018
Print Publication Date:
01 Aug 2018
Online Publication Date:
Aug 2018
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