Response to Rucaparib in BRCA-Mutant Metastatic Castration-Resistant Prostate Cancer Identified by Genomic Testing in the TRITON2 Study

Andrea Loehr; Akash Patnaik; David Campbell; Jeremy Shapiro; Alan H. Bryce; Ray McDermott; Brieuc Sautois; Nicholas J. Vogelzang; Richard M. Bambury; Eric Voog; Jingsong Zhang; Josep M. Piulats; Arif Hussain; Charles J. Ryan; Axel S. Merseburger; Gedske Daugaard; Axel Heidenreich; Karim Fizazi; Celestia S. Higano; Laurence E. Krieger; Cora N. Sternberg; Simon P. Watkins; Darrin Despain; Andrew D. Simmons; Melanie Dowson; Tony Golsorkhi; Simon Chowdhury; Wassim Abida

doi:10.1158/1078-0432.CCR-21-2199

Response to Rucaparib in BRCA-Mutant Metastatic Castration-Resistant Prostate Cancer Identified by Genomic Testing in the TRITON2 Study

Andrea Loehr, Akash Patnaik, David Campbell, Jeremy Shapiro, Alan H. Bryce, Ray McDermott, Brieuc Sautois, Nicholas J. Vogelzang, Richard M. Bambury, Eric Voog, Jingsong Zhang, Josep M. Piulats, Arif Hussain, Charles J. Ryan, Axel S. Merseburger, Gedske Daugaard, Axel Heidenreich, Karim Fizazi, Celestia S. Higano, Laurence E. KriegerCora N. Sternberg, Simon P. Watkins, Darrin Despain, Andrew D. Simmons, Melanie Dowson, Tony Golsorkhi, Simon Chowdhury, Wassim Abida^*

^*Corresponding author for this work

18 Citations (Scopus)

Abstract

Purpose: The PARP inhibitor rucaparib is approved in the United States for patients with metastatic castration-resistant prostate cancer (mCRPC) and a deleterious germline and/or somatic BRCA1 or BRCA2 (BRCA) alteration. While sequencing of tumor tissue is considered the standard for identifying patients with BRCA alterations (BRCA ), plasma profiling may provide a minimally invasive option to select patients for rucaparib treatment. Here, we report clinical efficacy in patients with BRCA mCRPC identified through central plasma, central tissue, or local genomic testing and enrolled in TRITON2. Patients and Methods: Patients had progressed after nextgeneration androgen receptor-directed and taxane-based therapies for mCRPC and had BRCA alterations identified by central sequencing of plasma and/or tissue samples or local genomic testing. Concordance of plasma/tissue BRCA status and objective response rate and prostate-specific antigen (PSA) response rates were summarized. Results: TRITON2 enrolled 115 patients with BRCA identified by central plasma (n 34), central tissue (n 37), or local (n 44) testing. Plasma/tissue concordance was determined in 38 patients with paired samples and was 47% in 19 patients with a somatic BRCA alteration. No statistically significant differences were observed between objective and PSA response rates to rucaparib across the 3 assay groups. Patients unable to provide tissue samples and tested solely by plasma assay responded at rates no different from patients identified as BRCA by tissue testing. Conclusions: Plasma, tissue, and local testing of mCRPC patients can be used to identify men with BRCA mCRPC who can benefit from treatment with the PARP inhibitor rucaparib.

Original language	English
Journal	Clinical Cancer Research
Volume	27
Issue number	24
Pages (from-to)	6677-6686
Number of pages	10
ISSN	1078-0432
DOIs	https://doi.org/10.1158/1078-0432.CCR-21-2199
Publication status	Published - 15.12.2021

Funding

Research support for the study: This study was funded by Clovis Oncology, Inc. A. Loehr reports other support from Clovis Oncology, Inc., during the conduct of the study. A. Patnaik reports other support from Clovis Oncology, Inc., during the conduct of the study as well as grants from Bristol-Myers Squibb and other support from Progenics, Laekna Inc, Exelixis, Prime, Jounce Therapeutics, Janssen, and Merck outside the submitted work. J. Shapiro has served in a consulting or advisory role for Amgen, Astellas, Ipsen, Merck, and Roche and received financial support for travel from Amgen and Merck. A.H. Bryce reports personal fees from Merck, Astellas, Bayer, and Pfizer outside the submitted work. R. McDermott reports personal fees from Clovis Oncology, Inc., during the conduct of the study as well as personal fees from Bayer, MSD, Sanofi, Janssen, Astellas, BMS, Pfizer, and Novartis outside the submitted work. B. Sautois reports other support from Clovis Oncology, Inc., during the conduct of the study as well as personal fees from Janssen, Astellas, and Sanofi outside the submitted work. N.J. Vogelzang reports personal fees from Clovis Oncology, Inc., AstraZeneca, and Pfizer during the conduct of the study. R.M. Bambury reports educational grant support and honoraria from Pfizer, Roche, Janssen, Astellas, and BMS; in addition, R.M. Bambury is the co-founder of Portable Medical Technology Ltd. J. Zhang reports personal fees from Clovis Oncology, Inc., during the conduct of the study as well as grants and personal fees from Astellas, Bayer, and AstraZeneca and personal fees from Merck outside the submitted work. J.M. Piulats reports grants and personal fees from MSD, Pfizer, and Janssen; grants from BeiGene; and nonfinancial support from Clovis Oncology, Inc., during the conduct of the study as well as personal fees from Astellas, Bayer, and Roche and grants, personal fees, and nonfinancial support from BMS outside the submitted work. A. Hussain reports other support from Clovis Oncology, Inc., during the conduct of the study as well as personal fees from Bayer, Merck, and Aveo Pharmaceuticals outside the submitted work; in addition, A. Hussain serves as institutional principal investigator (PI) on several sponsored clinical trials in prostate cancer, renal cancer, and bladder cancer where the respective sponsors provide funding directly to the institution (University of Maryland Greenebaum Comprehensive Cancer Center) to help defray costs of running the clinical trials. C.J. Ryan has received research support from Clovis Oncology, Inc., and has served as a consultant for AstraZeneca and Bayer. A.S. Merseburger reports personal fees, nonfinancial support, and other support from Clovis Oncology, Inc., during the conduct of the study as well as personal fees and nonfinancial support from AstraZeneca, Astellas, Janssen, Pfizer, and Ipsen outside the submitted work. G. Daugaard has served in a consulting or advisory role for Clovis Oncology, Inc., Astellas, AstraZeneca, Janssen, Merck, and Sanofi. A. Heidenreich reports personal fees from Clovis Oncology, Inc., during the conduct of the study as well as personal fees from Astellas, Bayer, Ipsen, Janssen, Pfizer, Takeda and MSD and grants and personal fees from Amgen and BMS outside the submitted work. K. Fizazi reports personal fees from Bayer, CureVac, and Orion and nonfinancial support from Astellas, Sanofi, Janssen, AstraZeneca, Clovis Oncology, Inc., and Novartis outside the submitted work. C.S. Higano reports grants and personal fees from Clovis Oncology, Inc., during the conduct of the study as well as personal fees and other support from Advanced Accelerator Applications, Blue Earth, Janssen, and Merck; grants from Aptevo, Emergent, Hoffman-LaRoche, and Medivation; grants, personal fees, and other support from Astellas, AstraZeneca, and Ferring; grants and personal fees from Bayer, Dendreon, Genetech, and Pfizer; and other support from Exelixis outside the submitted work. L.E. Krieger reports personal fees from Clovis Pharmaceuticals outside the submitted work. C.N. Sternberg reports personal fees from Clovis Oncology, Inc., during the conduct of the study as well as personal fees from Pfizer, BMS, Sanofi-Genzyme, MSD, Merck, Roche-Genentech, Incyte, Foundation Medicine, Immunomedics, Medscape, UroToday, Janssen, CCO Clinical, and NCI outside the submitted work. S.P. Watkins reports other support from Clovis Oncology, Inc., during the conduct of the study as well as other support from Clovis Oncology, Inc., outside the submitted work. D. Despain reports other support from Clovis Oncology, Inc., outside the submitted work; in addition, D. Despain is an employee of Clovis Oncology, Inc., the sponsor of rucaparib and the TRITON2 study. A.D. Simmons reports other support from Clovis Oncology, Inc., during the conduct of the study. M. Dowson reports personal fees from Clovis Oncology, Inc., outside the submitted work. T. Golsorkhi reports other support from Clovis Oncology, Inc., during the conduct of the study. S. Chowdhury reports grants and personal fees from Clovis Oncology, Inc., and personal fees from AstraZeneca, Novartis, Janssen, Bayer, Telix, Astellas, Huma, and Remedy Bio during the conduct of the study. W. Abida reports personal fees from Clovis Oncology, Inc., Roche, Medscape, Onclive, Clinical Education Alliance, Aptitude Health, Janssen, ORIC Pharmaceuticals, and Daiichi and other support from Clovis Oncology, Inc., during the conduct of the study as well as other support from AstraZeneca, Zenith Epigenetics, ORIC Pharmaceuticals, and Epizyme outside the submitted work. No disclosures were reported by the other authors. This work was funded by Clovis Oncology, Inc., and supported in part by the NCI Cancer Center Support Grant No. P30-CA008748, NCI Prostate Specialized Program of Research Excellence (SPORE) Grant No. P50-CA092629-16, Department of Defense Prostate Cancer Research Program Grant No. W81XWH-17-1-0124, and a Prostate Cancer Foundation Young Investigator Award (to W. Abida), and supported in part by a Prostate Cancer Foundation Challenge Award and NCI Prostate SPORE Grant No. P50-CA180995 (to A. Patnaik). Editorial support funded by Clovis Oncology, Inc., was provided by Shelly Lim and Stephen Bublitz of Ashfield MedComms, an Ashfield Health company.

UN SDGs

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

SDG 3 Good Health and Well-being

Research Areas and Centers

Research Area: Luebeck Integrated Oncology Network (LION)

DFG Research Classification Scheme

2.22-14 Hematology, Oncology
2.22-23 Reproductive Medicine, Urology

Access to Document

10.1158/1078-0432.CCR-21-2199

Cite this

Loehr, A., Patnaik, A., Campbell, D., Shapiro, J., Bryce, A. H., McDermott, R., Sautois, B., Vogelzang, N. J., Bambury, R. M., Voog, E., Zhang, J., Piulats, J. M., Hussain, A., Ryan, C. J., Merseburger, A. S., Daugaard, G., Heidenreich, A., Fizazi, K., Higano, C. S., ... Abida, W. (2021). Response to Rucaparib in BRCA-Mutant Metastatic Castration-Resistant Prostate Cancer Identified by Genomic Testing in the TRITON2 Study. Clinical Cancer Research, 27(24), 6677-6686. https://doi.org/10.1158/1078-0432.CCR-21-2199

@article{5af6a74cf1d2404d83aebf4ab9a59a63,

title = "Response to Rucaparib in BRCA-Mutant Metastatic Castration-Resistant Prostate Cancer Identified by Genomic Testing in the TRITON2 Study",

abstract = "Purpose: The PARP inhibitor rucaparib is approved in the United States for patients with metastatic castration-resistant prostate cancer (mCRPC) and a deleterious germline and/or somatic BRCA1 or BRCA2 (BRCA) alteration. While sequencing of tumor tissue is considered the standard for identifying patients with BRCA alterations (BRCA ), plasma profiling may provide a minimally invasive option to select patients for rucaparib treatment. Here, we report clinical efficacy in patients with BRCA mCRPC identified through central plasma, central tissue, or local genomic testing and enrolled in TRITON2. Patients and Methods: Patients had progressed after nextgeneration androgen receptor-directed and taxane-based therapies for mCRPC and had BRCA alterations identified by central sequencing of plasma and/or tissue samples or local genomic testing. Concordance of plasma/tissue BRCA status and objective response rate and prostate-specific antigen (PSA) response rates were summarized. Results: TRITON2 enrolled 115 patients with BRCA identified by central plasma (n 34), central tissue (n 37), or local (n 44) testing. Plasma/tissue concordance was determined in 38 patients with paired samples and was 47\% in 19 patients with a somatic BRCA alteration. No statistically significant differences were observed between objective and PSA response rates to rucaparib across the 3 assay groups. Patients unable to provide tissue samples and tested solely by plasma assay responded at rates no different from patients identified as BRCA by tissue testing. Conclusions: Plasma, tissue, and local testing of mCRPC patients can be used to identify men with BRCA mCRPC who can benefit from treatment with the PARP inhibitor rucaparib. ",

author = "Andrea Loehr and Akash Patnaik and David Campbell and Jeremy Shapiro and Bryce, \{Alan H.\} and Ray McDermott and Brieuc Sautois and Vogelzang, \{Nicholas J.\} and Bambury, \{Richard M.\} and Eric Voog and Jingsong Zhang and Piulats, \{Josep M.\} and Arif Hussain and Ryan, \{Charles J.\} and Merseburger, \{Axel S.\} and Gedske Daugaard and Axel Heidenreich and Karim Fizazi and Higano, \{Celestia S.\} and Krieger, \{Laurence E.\} and Sternberg, \{Cora N.\} and Watkins, \{Simon P.\} and Darrin Despain and Simmons, \{Andrew D.\} and Melanie Dowson and Tony Golsorkhi and Simon Chowdhury and Wassim Abida",

note = "Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",

year = "2021",

month = dec,

day = "15",

doi = "10.1158/1078-0432.CCR-21-2199",

language = "English",

volume = "27",

pages = "6677--6686",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "24",

}

Loehr, A, Patnaik, A, Campbell, D, Shapiro, J, Bryce, AH, McDermott, R, Sautois, B, Vogelzang, NJ, Bambury, RM, Voog, E, Zhang, J, Piulats, JM, Hussain, A, Ryan, CJ, Merseburger, AS, Daugaard, G, Heidenreich, A, Fizazi, K, Higano, CS, Krieger, LE, Sternberg, CN, Watkins, SP, Despain, D, Simmons, AD, Dowson, M, Golsorkhi, T, Chowdhury, S & Abida, W 2021, 'Response to Rucaparib in BRCA-Mutant Metastatic Castration-Resistant Prostate Cancer Identified by Genomic Testing in the TRITON2 Study', Clinical Cancer Research, vol. 27, no. 24, pp. 6677-6686. https://doi.org/10.1158/1078-0432.CCR-21-2199

TY - JOUR

T1 - Response to Rucaparib in BRCA-Mutant Metastatic Castration-Resistant Prostate Cancer Identified by Genomic Testing in the TRITON2 Study

AU - Loehr, Andrea

AU - Patnaik, Akash

AU - Campbell, David

AU - Shapiro, Jeremy

AU - Bryce, Alan H.

AU - McDermott, Ray

AU - Sautois, Brieuc

AU - Vogelzang, Nicholas J.

AU - Bambury, Richard M.

AU - Voog, Eric

AU - Zhang, Jingsong

AU - Piulats, Josep M.

AU - Hussain, Arif

AU - Ryan, Charles J.

AU - Merseburger, Axel S.

AU - Daugaard, Gedske

AU - Heidenreich, Axel

AU - Fizazi, Karim

AU - Higano, Celestia S.

AU - Krieger, Laurence E.

AU - Sternberg, Cora N.

AU - Watkins, Simon P.

AU - Despain, Darrin

AU - Simmons, Andrew D.

AU - Dowson, Melanie

AU - Golsorkhi, Tony

AU - Chowdhury, Simon

AU - Abida, Wassim

PY - 2021/12/15

Y1 - 2021/12/15

N2 - Purpose: The PARP inhibitor rucaparib is approved in the United States for patients with metastatic castration-resistant prostate cancer (mCRPC) and a deleterious germline and/or somatic BRCA1 or BRCA2 (BRCA) alteration. While sequencing of tumor tissue is considered the standard for identifying patients with BRCA alterations (BRCA ), plasma profiling may provide a minimally invasive option to select patients for rucaparib treatment. Here, we report clinical efficacy in patients with BRCA mCRPC identified through central plasma, central tissue, or local genomic testing and enrolled in TRITON2. Patients and Methods: Patients had progressed after nextgeneration androgen receptor-directed and taxane-based therapies for mCRPC and had BRCA alterations identified by central sequencing of plasma and/or tissue samples or local genomic testing. Concordance of plasma/tissue BRCA status and objective response rate and prostate-specific antigen (PSA) response rates were summarized. Results: TRITON2 enrolled 115 patients with BRCA identified by central plasma (n 34), central tissue (n 37), or local (n 44) testing. Plasma/tissue concordance was determined in 38 patients with paired samples and was 47% in 19 patients with a somatic BRCA alteration. No statistically significant differences were observed between objective and PSA response rates to rucaparib across the 3 assay groups. Patients unable to provide tissue samples and tested solely by plasma assay responded at rates no different from patients identified as BRCA by tissue testing. Conclusions: Plasma, tissue, and local testing of mCRPC patients can be used to identify men with BRCA mCRPC who can benefit from treatment with the PARP inhibitor rucaparib.

AB - Purpose: The PARP inhibitor rucaparib is approved in the United States for patients with metastatic castration-resistant prostate cancer (mCRPC) and a deleterious germline and/or somatic BRCA1 or BRCA2 (BRCA) alteration. While sequencing of tumor tissue is considered the standard for identifying patients with BRCA alterations (BRCA ), plasma profiling may provide a minimally invasive option to select patients for rucaparib treatment. Here, we report clinical efficacy in patients with BRCA mCRPC identified through central plasma, central tissue, or local genomic testing and enrolled in TRITON2. Patients and Methods: Patients had progressed after nextgeneration androgen receptor-directed and taxane-based therapies for mCRPC and had BRCA alterations identified by central sequencing of plasma and/or tissue samples or local genomic testing. Concordance of plasma/tissue BRCA status and objective response rate and prostate-specific antigen (PSA) response rates were summarized. Results: TRITON2 enrolled 115 patients with BRCA identified by central plasma (n 34), central tissue (n 37), or local (n 44) testing. Plasma/tissue concordance was determined in 38 patients with paired samples and was 47% in 19 patients with a somatic BRCA alteration. No statistically significant differences were observed between objective and PSA response rates to rucaparib across the 3 assay groups. Patients unable to provide tissue samples and tested solely by plasma assay responded at rates no different from patients identified as BRCA by tissue testing. Conclusions: Plasma, tissue, and local testing of mCRPC patients can be used to identify men with BRCA mCRPC who can benefit from treatment with the PARP inhibitor rucaparib.

UR - https://www.scopus.com/pages/publications/85122367564

U2 - 10.1158/1078-0432.CCR-21-2199

DO - 10.1158/1078-0432.CCR-21-2199

M3 - Journal articles

C2 - 34598946

AN - SCOPUS:85122367564

SN - 1078-0432

VL - 27

SP - 6677

EP - 6686

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 24

ER -

Response to Rucaparib in BRCA-Mutant Metastatic Castration-Resistant Prostate Cancer Identified by Genomic Testing in the TRITON2 Study

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