Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations

Alexandra O. Sokolova; Catherine H. Marshall; Rebeca Lozano; Roman Gulati; Elisa M. Ledet; Navonil De Sarkar; Petros Grivas; Celestia S. Higano; Bruce Montgomery; Peter S. Nelson; David Olmos; Vadim Sokolov; Michael T. Schweizer; Todd A. Yezefski; Evan Y. Yu; Channing J. Paller; Oliver Sartor; Elena Castro; Emmanuel S. Antonarakis; Heather H. Cheng

doi:10.1002/pros.24236

Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations

Alexandra O. Sokolova, Catherine H. Marshall, Rebeca Lozano, Roman Gulati, Elisa M. Ledet, Navonil De Sarkar, Petros Grivas, Celestia S. Higano, Bruce Montgomery, Peter S. Nelson, David Olmos, Vadim Sokolov, Michael T. Schweizer, Todd A. Yezefski, Evan Y. Yu, Channing J. Paller, Oliver Sartor, Elena Castro, Emmanuel S. Antonarakis, Heather H. Cheng

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

BACKGROUND: Among men with metastatic prostate cancer, about 10% have germline alterations in DNA damage response genes. Most studies have examined BRCA2 alone or an aggregate of BRCA1/2 and ATM. Emerging data suggest that ATM mutations may have distinct biology and warrant individual evaluation. The objective of this study is to determine whether response to prostate cancer systemic therapies differs between men with germline mutations in ATM (gATM) and BRCA2 (gBRCA2).

METHODS: This is an international multicenter retrospective matched cohort study of men with prostate cancer harboring gATM or gBRCA2. PSA 50 response (≥50% decline in prostate-specific antigen) was compared using Fisher's exact test.

RESULTS AND LIMITATIONS: The study included 45 gATM and 45 gBRCA2 patients, matched on stage and year of germline testing. Patients with gATM and gBRCA2 had similar age, Gleason grade, and PSA at diagnosis. We did not observe differences in PSA 50 responses to abiraterone, enzalutamide, or docetaxel in metastatic castration resistant prostate cancer between the two groups; however, 0/7 with gATM and 12/14 with gBRCA2 achieved PSA 50 response to PARPi (p < .001). Median (95% confidence interval) overall survival from diagnosis to death was 10.9 years (9.5-not reached) versus 9.9 years (7.1-not reached, p = .07) for the gATM and gBRCA2 cohorts, respectively. Limitations include the retrospective design and lack of mutation zygosity data.

CONCLUSIONS: Conventional therapies can be effective in gATM carriers and should be considered before PARPi, which shows limited efficacy in this group. Men with gATM mutations warrant prioritization for novel treatment strategies.

Original language	English (US)
Pages (from-to)	1382-1389
Number of pages	8
Journal	Prostate
Volume	81
Issue number	16
Early online date	Sep 13 2021
DOIs	https://doi.org/10.1002/pros.24236
State	Published - Dec 1 2021
Externally published	Yes

Bibliographical note

Funding Information:
Michael T. Schweizer: Paid consultant for Janssen and Resverlogix. Research funding from Bristol Myers Squibb, Merck, Immunomedics, Janssen, AstraZeneca, Pfizer, Madison Vaccines, Tmunity and Hoffman‐La Roche.

Funding Information:
We thank Agnes Gawne for data collection assistance. We gratefully acknowledge funding support from the Institute for Prostate Cancer Research, Prostate Cancer Foundation, Washington State Medical Oncology Society, Advancing Cancer Treatment, Patrick Walsh Prostate Cancer Research Fund, and NCI award numbers CA097186 (Pacific Northwest Prostate Cancer SPORE), P30 CA015704, P30 CA006973‐52, R01 CA238384, R50 CA221836, and T32CA009515; PCF YI VALor award, CDMRP Awards W81XWH‐17‐2‐0043, W81XWH‐15‐1‐0430, PC170503, PC171001, DOD EIRA award W81XWH‐17‐1‐0380 and the DOD Clinical Consortium award W81XWH‐16‐PCRP‐CCRSA.

Funding Information:
Petros Grivas: received grants from Bavarian Nordic, Bristol Myers Squibb, Clovis Oncology, Debiopharm, EMD Serono, GlaxoSmithKline, Immunomedics, Kure It Cancer Research, Merck & Co., Mirati Therapeutics, Pfizer, QED Therapeutics. Dr. Grivas has received consulting fees from AstraZeneca, Astellas Pharma, Bayer, Bristol Myers Squibb, Clovis Oncology, Dyania Health, Driver, EMD Serono, Exelixis, Foundation Medicine, Genentech/Roche, Genzyme, GlaxoSmithKline, Guardant Health, Heron Therapeutics, Immunomedics/Gilead, Infinity Pharmaceuticals, Janssen, Merck & Co., Mirati Therapeutics, Pfizer, QED Therapeutics, Regeneron Pharmaceuticals, Seattle Genetics, 4D Pharma PLC.Celestia S. Higano: Institutional research funding: Aptevo, Aragon, Astellas, AstraZeneca, Clovis, Dendreon, eFFECTOR Therapeutics, Emergent, Ferring, Genentech, Hoffman‐La roche, Medivation, Pfizer; Consulting, scientific advisory boards: Astellas, Bayer, Blue Earth Diagnositics, Clovis, Dendreon, Ferring, Hinova, Janssen, Merck, Orion, Pfizer, Tolmar, Carrick Therapeutics, Novartis, Genentech; Other: spouse holds stock and former officer of CTI Biopharma.

Publisher Copyright:
© 2021 Wiley Periodicals LLC

Keywords

ATM
BRCA2
PARPi
abiraterone
docetaxel
enzalutamide
germline
homologous recombination deficiency
platinum

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/pros.24236

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Sokolova, A. O., Marshall, C. H., Lozano, R., Gulati, R., Ledet, E. M., De Sarkar, N., Grivas, P., Higano, C. S., Montgomery, B., Nelson, P. S., Olmos, D., Sokolov, V., Schweizer, M. T., Yezefski, T. A., Yu, E. Y., Paller, C. J., Sartor, O., Castro, E., Antonarakis, E. S., & Cheng, H. H. (2021). Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations. Prostate, 81(16), 1382-1389. https://doi.org/10.1002/pros.24236

Sokolova, AO, Marshall, CH, Lozano, R, Gulati, R, Ledet, EM, De Sarkar, N, Grivas, P, Higano, CS, Montgomery, B, Nelson, PS, Olmos, D, Sokolov, V, Schweizer, MT, Yezefski, TA, Yu, EY, Paller, CJ, Sartor, O, Castro, E, Antonarakis, ES & Cheng, HH 2021, 'Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations', Prostate, vol. 81, no. 16, pp. 1382-1389. https://doi.org/10.1002/pros.24236

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title = "Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations",

abstract = "BACKGROUND: Among men with metastatic prostate cancer, about 10% have germline alterations in DNA damage response genes. Most studies have examined BRCA2 alone or an aggregate of BRCA1/2 and ATM. Emerging data suggest that ATM mutations may have distinct biology and warrant individual evaluation. The objective of this study is to determine whether response to prostate cancer systemic therapies differs between men with germline mutations in ATM (gATM) and BRCA2 (gBRCA2).METHODS: This is an international multicenter retrospective matched cohort study of men with prostate cancer harboring gATM or gBRCA2. PSA 50 response (≥50% decline in prostate-specific antigen) was compared using Fisher's exact test. RESULTS AND LIMITATIONS: The study included 45 gATM and 45 gBRCA2 patients, matched on stage and year of germline testing. Patients with gATM and gBRCA2 had similar age, Gleason grade, and PSA at diagnosis. We did not observe differences in PSA 50 responses to abiraterone, enzalutamide, or docetaxel in metastatic castration resistant prostate cancer between the two groups; however, 0/7 with gATM and 12/14 with gBRCA2 achieved PSA 50 response to PARPi (p < .001). Median (95% confidence interval) overall survival from diagnosis to death was 10.9 years (9.5-not reached) versus 9.9 years (7.1-not reached, p = .07) for the gATM and gBRCA2 cohorts, respectively. Limitations include the retrospective design and lack of mutation zygosity data. CONCLUSIONS: Conventional therapies can be effective in gATM carriers and should be considered before PARPi, which shows limited efficacy in this group. Men with gATM mutations warrant prioritization for novel treatment strategies.",

keywords = "ATM, BRCA2, PARPi, abiraterone, docetaxel, enzalutamide, germline, homologous recombination deficiency, platinum",

author = "Sokolova, {Alexandra O.} and Marshall, {Catherine H.} and Rebeca Lozano and Roman Gulati and Ledet, {Elisa M.} and {De Sarkar}, Navonil and Petros Grivas and Higano, {Celestia S.} and Bruce Montgomery and Nelson, {Peter S.} and David Olmos and Vadim Sokolov and Schweizer, {Michael T.} and Yezefski, {Todd A.} and Yu, {Evan Y.} and Paller, {Channing J.} and Oliver Sartor and Elena Castro and Antonarakis, {Emmanuel S.} and Cheng, {Heather H.}",

note = "Funding Information: Michael T. Schweizer: Paid consultant for Janssen and Resverlogix. Research funding from Bristol Myers Squibb, Merck, Immunomedics, Janssen, AstraZeneca, Pfizer, Madison Vaccines, Tmunity and Hoffman‐La Roche. Funding Information: We thank Agnes Gawne for data collection assistance. We gratefully acknowledge funding support from the Institute for Prostate Cancer Research, Prostate Cancer Foundation, Washington State Medical Oncology Society, Advancing Cancer Treatment, Patrick Walsh Prostate Cancer Research Fund, and NCI award numbers CA097186 (Pacific Northwest Prostate Cancer SPORE), P30 CA015704, P30 CA006973‐52, R01 CA238384, R50 CA221836, and T32CA009515; PCF YI VALor award, CDMRP Awards W81XWH‐17‐2‐0043, W81XWH‐15‐1‐0430, PC170503, PC171001, DOD EIRA award W81XWH‐17‐1‐0380 and the DOD Clinical Consortium award W81XWH‐16‐PCRP‐CCRSA. Funding Information: Petros Grivas: received grants from Bavarian Nordic, Bristol Myers Squibb, Clovis Oncology, Debiopharm, EMD Serono, GlaxoSmithKline, Immunomedics, Kure It Cancer Research, Merck & Co., Mirati Therapeutics, Pfizer, QED Therapeutics. Dr. Grivas has received consulting fees from AstraZeneca, Astellas Pharma, Bayer, Bristol Myers Squibb, Clovis Oncology, Dyania Health, Driver, EMD Serono, Exelixis, Foundation Medicine, Genentech/Roche, Genzyme, GlaxoSmithKline, Guardant Health, Heron Therapeutics, Immunomedics/Gilead, Infinity Pharmaceuticals, Janssen, Merck & Co., Mirati Therapeutics, Pfizer, QED Therapeutics, Regeneron Pharmaceuticals, Seattle Genetics, 4D Pharma PLC.Celestia S. Higano: Institutional research funding: Aptevo, Aragon, Astellas, AstraZeneca, Clovis, Dendreon, eFFECTOR Therapeutics, Emergent, Ferring, Genentech, Hoffman‐La roche, Medivation, Pfizer; Consulting, scientific advisory boards: Astellas, Bayer, Blue Earth Diagnositics, Clovis, Dendreon, Ferring, Hinova, Janssen, Merck, Orion, Pfizer, Tolmar, Carrick Therapeutics, Novartis, Genentech; Other: spouse holds stock and former officer of CTI Biopharma. Publisher Copyright: {\textcopyright} 2021 Wiley Periodicals LLC",

year = "2021",

month = dec,

day = "1",

doi = "10.1002/pros.24236",

language = "English (US)",

volume = "81",

pages = "1382--1389",

journal = "Prostate",

issn = "0270-4137",

publisher = "John Wiley and Sons Inc.",

number = "16",

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TY - JOUR

T1 - Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations

AU - Sokolova, Alexandra O.

AU - Marshall, Catherine H.

AU - Lozano, Rebeca

AU - Gulati, Roman

AU - Ledet, Elisa M.

AU - De Sarkar, Navonil

AU - Grivas, Petros

AU - Higano, Celestia S.

AU - Montgomery, Bruce

AU - Nelson, Peter S.

AU - Olmos, David

AU - Sokolov, Vadim

AU - Schweizer, Michael T.

AU - Yezefski, Todd A.

AU - Yu, Evan Y.

AU - Paller, Channing J.

AU - Sartor, Oliver

AU - Castro, Elena

AU - Antonarakis, Emmanuel S.

AU - Cheng, Heather H.

N1 - Funding Information: Michael T. Schweizer: Paid consultant for Janssen and Resverlogix. Research funding from Bristol Myers Squibb, Merck, Immunomedics, Janssen, AstraZeneca, Pfizer, Madison Vaccines, Tmunity and Hoffman‐La Roche. Funding Information: We thank Agnes Gawne for data collection assistance. We gratefully acknowledge funding support from the Institute for Prostate Cancer Research, Prostate Cancer Foundation, Washington State Medical Oncology Society, Advancing Cancer Treatment, Patrick Walsh Prostate Cancer Research Fund, and NCI award numbers CA097186 (Pacific Northwest Prostate Cancer SPORE), P30 CA015704, P30 CA006973‐52, R01 CA238384, R50 CA221836, and T32CA009515; PCF YI VALor award, CDMRP Awards W81XWH‐17‐2‐0043, W81XWH‐15‐1‐0430, PC170503, PC171001, DOD EIRA award W81XWH‐17‐1‐0380 and the DOD Clinical Consortium award W81XWH‐16‐PCRP‐CCRSA. Funding Information: Petros Grivas: received grants from Bavarian Nordic, Bristol Myers Squibb, Clovis Oncology, Debiopharm, EMD Serono, GlaxoSmithKline, Immunomedics, Kure It Cancer Research, Merck & Co., Mirati Therapeutics, Pfizer, QED Therapeutics. Dr. Grivas has received consulting fees from AstraZeneca, Astellas Pharma, Bayer, Bristol Myers Squibb, Clovis Oncology, Dyania Health, Driver, EMD Serono, Exelixis, Foundation Medicine, Genentech/Roche, Genzyme, GlaxoSmithKline, Guardant Health, Heron Therapeutics, Immunomedics/Gilead, Infinity Pharmaceuticals, Janssen, Merck & Co., Mirati Therapeutics, Pfizer, QED Therapeutics, Regeneron Pharmaceuticals, Seattle Genetics, 4D Pharma PLC.Celestia S. Higano: Institutional research funding: Aptevo, Aragon, Astellas, AstraZeneca, Clovis, Dendreon, eFFECTOR Therapeutics, Emergent, Ferring, Genentech, Hoffman‐La roche, Medivation, Pfizer; Consulting, scientific advisory boards: Astellas, Bayer, Blue Earth Diagnositics, Clovis, Dendreon, Ferring, Hinova, Janssen, Merck, Orion, Pfizer, Tolmar, Carrick Therapeutics, Novartis, Genentech; Other: spouse holds stock and former officer of CTI Biopharma. Publisher Copyright: © 2021 Wiley Periodicals LLC

PY - 2021/12/1

Y1 - 2021/12/1

N2 - BACKGROUND: Among men with metastatic prostate cancer, about 10% have germline alterations in DNA damage response genes. Most studies have examined BRCA2 alone or an aggregate of BRCA1/2 and ATM. Emerging data suggest that ATM mutations may have distinct biology and warrant individual evaluation. The objective of this study is to determine whether response to prostate cancer systemic therapies differs between men with germline mutations in ATM (gATM) and BRCA2 (gBRCA2).METHODS: This is an international multicenter retrospective matched cohort study of men with prostate cancer harboring gATM or gBRCA2. PSA 50 response (≥50% decline in prostate-specific antigen) was compared using Fisher's exact test. RESULTS AND LIMITATIONS: The study included 45 gATM and 45 gBRCA2 patients, matched on stage and year of germline testing. Patients with gATM and gBRCA2 had similar age, Gleason grade, and PSA at diagnosis. We did not observe differences in PSA 50 responses to abiraterone, enzalutamide, or docetaxel in metastatic castration resistant prostate cancer between the two groups; however, 0/7 with gATM and 12/14 with gBRCA2 achieved PSA 50 response to PARPi (p < .001). Median (95% confidence interval) overall survival from diagnosis to death was 10.9 years (9.5-not reached) versus 9.9 years (7.1-not reached, p = .07) for the gATM and gBRCA2 cohorts, respectively. Limitations include the retrospective design and lack of mutation zygosity data. CONCLUSIONS: Conventional therapies can be effective in gATM carriers and should be considered before PARPi, which shows limited efficacy in this group. Men with gATM mutations warrant prioritization for novel treatment strategies.

AB - BACKGROUND: Among men with metastatic prostate cancer, about 10% have germline alterations in DNA damage response genes. Most studies have examined BRCA2 alone or an aggregate of BRCA1/2 and ATM. Emerging data suggest that ATM mutations may have distinct biology and warrant individual evaluation. The objective of this study is to determine whether response to prostate cancer systemic therapies differs between men with germline mutations in ATM (gATM) and BRCA2 (gBRCA2).METHODS: This is an international multicenter retrospective matched cohort study of men with prostate cancer harboring gATM or gBRCA2. PSA 50 response (≥50% decline in prostate-specific antigen) was compared using Fisher's exact test. RESULTS AND LIMITATIONS: The study included 45 gATM and 45 gBRCA2 patients, matched on stage and year of germline testing. Patients with gATM and gBRCA2 had similar age, Gleason grade, and PSA at diagnosis. We did not observe differences in PSA 50 responses to abiraterone, enzalutamide, or docetaxel in metastatic castration resistant prostate cancer between the two groups; however, 0/7 with gATM and 12/14 with gBRCA2 achieved PSA 50 response to PARPi (p < .001). Median (95% confidence interval) overall survival from diagnosis to death was 10.9 years (9.5-not reached) versus 9.9 years (7.1-not reached, p = .07) for the gATM and gBRCA2 cohorts, respectively. Limitations include the retrospective design and lack of mutation zygosity data. CONCLUSIONS: Conventional therapies can be effective in gATM carriers and should be considered before PARPi, which shows limited efficacy in this group. Men with gATM mutations warrant prioritization for novel treatment strategies.

KW - ATM

KW - BRCA2

KW - PARPi

KW - abiraterone

KW - docetaxel

KW - enzalutamide

KW - germline

KW - homologous recombination deficiency

KW - platinum

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UR - http://www.scopus.com/inward/citedby.url?scp=85114718067&partnerID=8YFLogxK

U2 - 10.1002/pros.24236

DO - 10.1002/pros.24236

M3 - Article

C2 - 34516663

AN - SCOPUS:85114718067

SN - 0270-4137

VL - 81

SP - 1382

EP - 1389

JO - Prostate

JF - Prostate

IS - 16

ER -

Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations

Abstract

Bibliographical note

Keywords

UN SDGs

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