Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes: correlative analysis of the E3805 CHAARTED trial

A. A. Hamid; H. C. Huang; V. Wang; Y. H. Chen; F. Feng; R. Den; G. Attard; E. M. Van Allen; P. T. Tran; D. E. Spratt; R. Dittamore; E. Davicioni; G. Liu; R. DiPaola; M. A. Carducci; C. J. Sweeney

doi:10.1016/j.annonc.2021.06.003

Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes: correlative analysis of the E3805 CHAARTED trial

A. A. Hamid
, H. C. Huang
, V. Wang
, Y. H. Chen
, F. Feng
, R. Den
, G. Attard
, E. M. Van Allen
, P. T. Tran
, D. E. Spratt
, R. Dittamore
, E. Davicioni
, G. Liu
, R. DiPaola
, M. A. Carducci
, C. J. Sweeney

Producción científica: Article › revisión exhaustiva

64 Citas (Scopus)

Resumen

Background: The phase III CHAARTED trial established upfront androgen-deprivation therapy (ADT) plus docetaxel (D) as a standard for metastatic hormone-sensitive prostate cancer (mHSPC) based on meaningful improvement in overall survival (OS). Biological prognostic markers of outcomes and predictors of chemotherapy benefit are undefined. Patients and methods: Whole transcriptomic profiling was performed on primary PC tissue obtained from patients enrolled in CHAARTED prior to systemic therapy. We adopted an a priori analytical plan to test defined RNA signatures and their associations with HSPC clinical phenotypes and outcomes. Multivariable analyses (MVAs) were adjusted for age, Eastern Cooperative Oncology Group status, de novo metastasis presentation, volume of disease, and treatment arm. The primary endpoint was OS; the secondary endpoint was time to castration-resistant PC. Results: The analytic cohort of 160 patients demonstrated marked differences in transcriptional profile compared with localized PC, with a predominance of luminal B (50%) and basal (48%) subtypes, lower androgen receptor activity (AR-A), and high Decipher risk disease. Luminal B subtype was associated with poorer prognosis on ADT alone but benefited significantly from ADT + D [OS: hazard ratio (HR) 0.45; P = 0.007], in contrast to basal subtype which showed no OS benefit (HR 0.85; P = 0.58), even in those with high-volume disease. Higher Decipher risk and lower AR-A were significantly associated with poorer OS in MVA. In addition, higher Decipher risk showed greater improvements in OS with ADT + D (HR 0.41; P = 0.015). Conclusion: This study demonstrates the utility of transcriptomic subtyping to guide prognostication in mHSPC and potential selection of patients for chemohormonal therapy, and provides proof of concept for the possibility of biomarker-guided selection of established combination therapies in mHSPC.

Idioma original	English
Páginas (desde-hasta)	1157-1166
Número de páginas	10
Publicación	Annals of Oncology
Volumen	32
N.º	9
DOI	https://doi.org/10.1016/j.annonc.2021.06.003
Estado	Published - sept 2021

Nota bibliográfica

Publisher Copyright:
© 2021 The Authors

Financiación

This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O’Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820 , U10CA180794 , UG1CA233160 , UG1CA233180 , UG1CA233196 , UG1CA233277 , UG1CA233341 . The study was also supported by Sanofi . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Mention of trade names, commercial products, or organizations does not imply endorsement by the US government. Decipher Biosciences: In-kind support for Decipher microarray profiling and data generation. AAH: supported by Prostate Cancer Foundation Young Investigator Award [grant number 18YOUN07 ]; National Health and Medical Research Council Australia (no grant number), Department of Defense Early Investigator Research Award [grant number W81XWH2010055 ]. CJS: Supported by National Institutes of Health Research Project Grant Program [grant number NIH R01 CA238020-01A1 ]. This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, U10CA180794, UG1CA233160, UG1CA233180, UG1CA233196, UG1CA233277, UG1CA233341. The study was also supported by Sanofi. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Mention of trade names, commercial products, or organizations does not imply endorsement by the US government. Decipher Biosciences: In-kind support for Decipher microarray profiling and data generation. AAH: supported by Prostate Cancer Foundation Young Investigator Award [grant number 18YOUN07]; National Health and Medical Research Council Australia (no grant number), Department of Defense Early Investigator Research Award [grant number W81XWH2010055]. CJS: Supported by National Institutes of Health Research Project Grant Program [grant number NIH R01 CA238020-01A1]. A.A.H reports consulting fees from Merck Sharp & Dohme. H-C.H. R.D. and E.D. are employees of Decipher Biosciences. F.F. reports receiving fees for serving as a consultant from Janssen during the conduct of the study, Celgene, Blue Earth Diagnostics, Astellas, Myovant, Roivant, Genentech, and Bayer; being a co-founder having stock options in PFS Genomics; and having stock options and serving on the scientific advisory board of SerImmune Stock outside the submitted work. G.A. reports personal fees, research support and travel support from Janssen during the conduct of the study; personal fees and/or travel support from Astellas, Pfizer, Millennium Pharmaceuticals, Ipsen, Ventana, Veridex, Novartis, Abbott Laboratories, ESSA Pharmaceuticals, Bayer Healthcare Pharmaceuticals, Takeda and Sanofi-Aventis and research funding from AstraZeneca, Innocrin Pharma and Arno Therapeutics outside the submitted work; in addition, G.A.?s former employer, The Institute of Cancer Research (ICR), receives royalty income from abiraterone acetate and GA receives a share of this income through ICR's Rewards to Discoverers scheme. E.M.V.A reports advisory/consulting role: Tango Therapeutics, Genome Medical, Invitae, Enara Bio, Janssen, Manifold Bio, Monte Rosa; research support: Novartis, BMS; equity: Tango Therapeutics, Genome Medical, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa; travel reimbursement: Roche/Genentech; patents: Institutional patents filed on chromatin mutations and immunotherapy response, and methods for clinical interpretation. P.T.T. reported receiving grants from RefleXion Medical, the Prostate Cancer Foundation, and Movember Foundation; personal fees from Noxopharm, Janssen-Taris Biomedical, Myovant, AstraZeneca, and RefleXion; grants from Astellas and Bayer Healthcare; and owning patent No. 9114158 (with royalties from Natsar Pharmaceuticals) outside the submitted work. D.E.S reports personal fees: Janssen, AstraZeneca, Bayer, Boston Scientific, and Blue Earth; funding: Janssen. G.L. is a co-founder and chief medical officer of AIQ Solutions (Madison, WI). M.A.A. reports past consultation for Pfizer, Astellas, and Exelixis, and current research funding from Arcus, Pfizer, and Merck. C.J.S. report consulting or advisory role: Sanofi, Janssen, Astellas Pharma, Bayer, Genentech, Pfizer, Lilly; research funding: Janssen Biotech (Inst), Astellas Pharma (Inst), Sanofi (Inst), Bayer (Inst), Sotio (Inst), Dendreon (Inst); patents, royalties, other intellectual property: Pathenolide (Indiana University): dimethylaminoparthenolide (Leuchemix); Exelixis: Abiraterone plus cabozantinib combination; stock or other ownership: Leuchemix.

Financiadores	Número del financiador
Bayer HealthCare Pharmaceuticals Inc.
Blue Earth Diagnostics
ESSA Pharmaceuticals
Millennium Pharmaceuticals Inc
Ventana
Veridex
National Institutes of Health (NIH)	R01 CA238020-01A1
U.S. Department of Defense	W81XWH2010055
National Childhood Cancer Registry – National Cancer Institute	U10CA180820, U10CA180794, UG1CA233160, UG1CA233180, UG1CA233341, UG1CA233196, UG1CA233277
Prostate Cancer Foundation	18YOUN07
Abbott Laboratories
Pfizer
Astellas Pharma Inc.
AstraZeneca
Merck
Novartis
Sanofi
Janssen Biotech
Celgene
University of Southern Indiana
RefleXion Medical
Takeda Pharmaceuticals U.S.A.
Movember Foundation
Janssen Pharmaceuticals
Exelixis Inc.
Ipsen Biopharmaceuticals
Government of South Australia
Bayer Fund
Children's Cancer Research Institute, Vienna
Bayer Healthcare Pharmaceutical	9114158
Australian National Health and Medical Research Council
Institute for Chemical Research, Kyoto University

ODS de las Naciones Unidas

Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

Good health and well being

ASJC Scopus subject areas

Hematology
Oncology

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10.1016/j.annonc.2021.06.003

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Hamid, A. A., Huang, H. C., Wang, V., Chen, Y. H., Feng, F., Den, R., Attard, G., Van Allen, E. M., Tran, P. T., Spratt, D. E., Dittamore, R., Davicioni, E., Liu, G., DiPaola, R., Carducci, M. A., & Sweeney, C. J. (2021). Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes: correlative analysis of the E3805 CHAARTED trial. Annals of Oncology, 32(9), 1157-1166. https://doi.org/10.1016/j.annonc.2021.06.003

@article{56c0780496a340a1b2a30b3684d6529a,

title = "Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes: correlative analysis of the E3805 CHAARTED trial",

abstract = "Background: The phase III CHAARTED trial established upfront androgen-deprivation therapy (ADT) plus docetaxel (D) as a standard for metastatic hormone-sensitive prostate cancer (mHSPC) based on meaningful improvement in overall survival (OS). Biological prognostic markers of outcomes and predictors of chemotherapy benefit are undefined. Patients and methods: Whole transcriptomic profiling was performed on primary PC tissue obtained from patients enrolled in CHAARTED prior to systemic therapy. We adopted an a priori analytical plan to test defined RNA signatures and their associations with HSPC clinical phenotypes and outcomes. Multivariable analyses (MVAs) were adjusted for age, Eastern Cooperative Oncology Group status, de novo metastasis presentation, volume of disease, and treatment arm. The primary endpoint was OS; the secondary endpoint was time to castration-resistant PC. Results: The analytic cohort of 160 patients demonstrated marked differences in transcriptional profile compared with localized PC, with a predominance of luminal B (50\%) and basal (48\%) subtypes, lower androgen receptor activity (AR-A), and high Decipher risk disease. Luminal B subtype was associated with poorer prognosis on ADT alone but benefited significantly from ADT + D [OS: hazard ratio (HR) 0.45; P = 0.007], in contrast to basal subtype which showed no OS benefit (HR 0.85; P = 0.58), even in those with high-volume disease. Higher Decipher risk and lower AR-A were significantly associated with poorer OS in MVA. In addition, higher Decipher risk showed greater improvements in OS with ADT + D (HR 0.41; P = 0.015). Conclusion: This study demonstrates the utility of transcriptomic subtyping to guide prognostication in mHSPC and potential selection of patients for chemohormonal therapy, and provides proof of concept for the possibility of biomarker-guided selection of established combination therapies in mHSPC.",

keywords = "Decipher, biomarker, docetaxel, gene expression profiling, metastatic prostate cancer",

author = "Hamid, \{A. A.\} and Huang, \{H. C.\} and V. Wang and Chen, \{Y. H.\} and F. Feng and R. Den and G. Attard and \{Van Allen\}, \{E. M.\} and Tran, \{P. T.\} and Spratt, \{D. E.\} and R. Dittamore and E. Davicioni and G. Liu and R. DiPaola and Carducci, \{M. A.\} and Sweeney, \{C. J.\}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = sep,

doi = "10.1016/j.annonc.2021.06.003",

language = "English",

volume = "32",

pages = "1157--1166",

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Hamid, AA, Huang, HC, Wang, V, Chen, YH, Feng, F, Den, R, Attard, G, Van Allen, EM, Tran, PT, Spratt, DE, Dittamore, R, Davicioni, E, Liu, G, DiPaola, R, Carducci, MA & Sweeney, CJ 2021, 'Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes: correlative analysis of the E3805 CHAARTED trial', Annals of Oncology, vol. 32, n.º 9, pp. 1157-1166. https://doi.org/10.1016/j.annonc.2021.06.003

TY - JOUR

T1 - Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes

T2 - correlative analysis of the E3805 CHAARTED trial

AU - Hamid, A. A.

AU - Huang, H. C.

AU - Wang, V.

AU - Chen, Y. H.

AU - Feng, F.

AU - Den, R.

AU - Attard, G.

AU - Van Allen, E. M.

AU - Tran, P. T.

AU - Spratt, D. E.

AU - Dittamore, R.

AU - Davicioni, E.

AU - Liu, G.

AU - DiPaola, R.

AU - Carducci, M. A.

AU - Sweeney, C. J.

PY - 2021/9

Y1 - 2021/9

N2 - Background: The phase III CHAARTED trial established upfront androgen-deprivation therapy (ADT) plus docetaxel (D) as a standard for metastatic hormone-sensitive prostate cancer (mHSPC) based on meaningful improvement in overall survival (OS). Biological prognostic markers of outcomes and predictors of chemotherapy benefit are undefined. Patients and methods: Whole transcriptomic profiling was performed on primary PC tissue obtained from patients enrolled in CHAARTED prior to systemic therapy. We adopted an a priori analytical plan to test defined RNA signatures and their associations with HSPC clinical phenotypes and outcomes. Multivariable analyses (MVAs) were adjusted for age, Eastern Cooperative Oncology Group status, de novo metastasis presentation, volume of disease, and treatment arm. The primary endpoint was OS; the secondary endpoint was time to castration-resistant PC. Results: The analytic cohort of 160 patients demonstrated marked differences in transcriptional profile compared with localized PC, with a predominance of luminal B (50%) and basal (48%) subtypes, lower androgen receptor activity (AR-A), and high Decipher risk disease. Luminal B subtype was associated with poorer prognosis on ADT alone but benefited significantly from ADT + D [OS: hazard ratio (HR) 0.45; P = 0.007], in contrast to basal subtype which showed no OS benefit (HR 0.85; P = 0.58), even in those with high-volume disease. Higher Decipher risk and lower AR-A were significantly associated with poorer OS in MVA. In addition, higher Decipher risk showed greater improvements in OS with ADT + D (HR 0.41; P = 0.015). Conclusion: This study demonstrates the utility of transcriptomic subtyping to guide prognostication in mHSPC and potential selection of patients for chemohormonal therapy, and provides proof of concept for the possibility of biomarker-guided selection of established combination therapies in mHSPC.

AB - Background: The phase III CHAARTED trial established upfront androgen-deprivation therapy (ADT) plus docetaxel (D) as a standard for metastatic hormone-sensitive prostate cancer (mHSPC) based on meaningful improvement in overall survival (OS). Biological prognostic markers of outcomes and predictors of chemotherapy benefit are undefined. Patients and methods: Whole transcriptomic profiling was performed on primary PC tissue obtained from patients enrolled in CHAARTED prior to systemic therapy. We adopted an a priori analytical plan to test defined RNA signatures and their associations with HSPC clinical phenotypes and outcomes. Multivariable analyses (MVAs) were adjusted for age, Eastern Cooperative Oncology Group status, de novo metastasis presentation, volume of disease, and treatment arm. The primary endpoint was OS; the secondary endpoint was time to castration-resistant PC. Results: The analytic cohort of 160 patients demonstrated marked differences in transcriptional profile compared with localized PC, with a predominance of luminal B (50%) and basal (48%) subtypes, lower androgen receptor activity (AR-A), and high Decipher risk disease. Luminal B subtype was associated with poorer prognosis on ADT alone but benefited significantly from ADT + D [OS: hazard ratio (HR) 0.45; P = 0.007], in contrast to basal subtype which showed no OS benefit (HR 0.85; P = 0.58), even in those with high-volume disease. Higher Decipher risk and lower AR-A were significantly associated with poorer OS in MVA. In addition, higher Decipher risk showed greater improvements in OS with ADT + D (HR 0.41; P = 0.015). Conclusion: This study demonstrates the utility of transcriptomic subtyping to guide prognostication in mHSPC and potential selection of patients for chemohormonal therapy, and provides proof of concept for the possibility of biomarker-guided selection of established combination therapies in mHSPC.

KW - Decipher

KW - biomarker

KW - docetaxel

KW - gene expression profiling

KW - metastatic prostate cancer

UR - https://www.scopus.com/pages/publications/85111011309

UR - https://www.scopus.com/pages/publications/85111011309#tab=citedBy

U2 - 10.1016/j.annonc.2021.06.003

DO - 10.1016/j.annonc.2021.06.003

M3 - Article

C2 - 34129855

AN - SCOPUS:85111011309

SN - 0923-7534

VL - 32

SP - 1157

EP - 1166

JO - Annals of Oncology

JF - Annals of Oncology

IS - 9

ER -

Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes: correlative analysis of the E3805 CHAARTED trial

Resumen

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Financiación

ODS de las Naciones Unidas

ASJC Scopus subject areas

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