Non-BRCA DNA Damage Repair Gene Alterations and Response to the PARP Inhibitor Rucaparib in Metastatic Castration-Resistant Prostate Cancer: Analysis from the Phase II TRITON2 Study

Wassim Abida, David Campbell, Akash Patnaik, Jeremy D. Shapiro, Brieuc Sautois, Nicholas J. Vogelzang, Eric G. Voog, Alan H. Bryce, Ray McDermott, Francesco Ricci, Julie Rowe, Jingsong Zhang, Josep Maria Piulats, Karim Fizazi, Axel S. Merseburger, Celestia S. Higano, Laurence E. Krieger, Charles J. Ryan, Felix Y. Feng, Andrew D. SimmonsAndrea Loehr, Darrin Despain, Melanie Dowson, Foad Green, Simon P. Watkins, Tony Golsorkhi, Simon Chowdhury

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Purpose: Genomic alterations in DNA damage repair (DDR) genes other than BRCA may confer synthetic lethality with PARP inhibition in metastatic castration-resistant prostate cancer (mCRPC). To test this hypothesis, the phase II TRITON2 study of rucaparib included patients with mCRPC and deleterious non-BRCA DDR gene alterations. Patients and Methods: TRITON2 enrolled patients who had progressed on one or two lines of next-generation androgen receptor–directed therapy and one taxane-based chemotherapy for mCRPC. Key endpoints were investigator-assessed radiographic response per modified RECIST/PCWG3 and PSA response (≥50% decrease from baseline). Results: TRITON2 enrolled 78 patients with a non-BRCA DDR gene alteration [ATM (n ¼ 49), CDK12 (n ¼ 15), CHEK2 (n ¼ 12), and other DDR genes (n ¼ 14)]. Among patients evaluable for each endpoint, radiographic and PSA responses were observed in a limited number of patients with an alteration in ATM [2/19 (10.5%) and 2/49 (4.1%), respectively], CDK12 [0/10 (0%) and 1/15 (6.7%), respectively], or CHEK2 [1/9 (11.1%) and 2/12 (16.7%), respectively], including no radiographic or PSA responses in 11 patients with confirmed biallelic ATM loss or 11 patients with ATM germline mutations. Responses were observed in patients with alterations in the DDR genes PALB2, FANCA, BRIP1, and RAD51B. Conclusions: In this prospective, genomics-driven study of rucaparib in mCRPC, we found limited radiographic/PSA responses to PARP inhibition in men with alterations in ATM, CDK12, or CHEK2. However, patients with alterations in other DDR-associated genes (e.g., PALB2) may benefit from PARP inhibition.

Original languageEnglish (US)
Pages (from-to)2487-2496
Number of pages10
JournalClinical Cancer Research
Volume26
Issue number11
DOIs
StatePublished - Jun 1 2020

Bibliographical note

Funding Information:
TRITON2 was designed by the funder and the first/last authors (W. Abida and S. Chowdhury). This article was written by the authors, with medical writing and copy editing support paid for by the funder. Data were collected by the investigators, analyzed by the funder, and interpreted by all authors. All authors had full access to all trial data and had final responsibility for the decision to submit for publication. Medical writing and editorial support funded by Clovis Oncology were provided by Nathan Yardley and Frederique H. Evans of Ashfield Healthcare Communications. W. Abida is funded by National Cancer Institute (NCI) Cancer Center Support Grant P30 CA 008748, NCI Prostate Specialized Program of Research Excellence (SPORE) grant P50 CA092629-16; Department of Defense Prostate Cancer Research Program grant W81XWH-17-1-0124, and a Prostate Cancer Foundation Young Investigator Award.

Funding Information:
W. Abida is an employee/paid consultant for Clovis Oncology, Janssen, ORIC Pharmaceuticals, and MORE Health. A. Patnaik is an employee/paid consultant for and reports receiving commercial research grants from Clovis. B. Sautois is an employee/paid consultant for Clovis Oncology, Astellas, Janssen, and Sanofi, and reports receiving other commercial research support from Janssen. A.H. Bryce reports receiving speakers bureau honoraria from Astellas and OncLive. R. McDermott is an employee/paid consultant for Bayer, Pfizer, and Janssen, and reports receiving other commercial research support from Bristol-Myers Squibb, Clovis, Amgen, Merck, and Bayer. J. Rowe reports receiving speakers bureau honoraria from Dendreon. J. Zhang is an employee/paid consultant for Seattle Genetics, Clovis Oncology, Bayer, Janssen, and Dendreon, and reports receiving speakers bureau honoraria from Sanofi and Merck. J.M. Piulats is an employee/paid consultant for Roche, reports receiving commercial research grants from Janssen, Bristol-Myers Squibb, Merck Sharp & Dhome (MSD), Pfizer, and AstraZeneca, and speakers bureau honoraria from Bristol-Myers Squibb, Janssen, Astellas, VCN Biotech, BeiGene, Merck Sharp & Dhome (MSD), and AstraZeneca. K. Fizazi is an advisory board member/unpaid consultant for Clovis, Orion, AstraZeneca, Bayer, CureVac, Janssen, Sanofi, Astellas, Amgen, and ESSA. A.S. Merseburger reports receiving other commercial research support from Clovis Oncology, speakers bureau honoraria from Janssen, Astellas, Bayer, GlaxoSmithKline, Ipsen, Novartis, Pfizer, TEVA, and Wyeth, and is an advisory board member/unpaid consultant for Astellas, Bayer, GlaxoSmithKline, Hexal, and Sanofi Aventis. C.S. Higano is an employee/paid consultant for Pfizer, Janssen, Bayer, Blue Earth Diagnostics, Clovis, Ferring, Carrick Therapeutics, Merck, Hinova, Orion, Myriad, Tolmar, and Astellas. L.E. Krieger is an employee/paid consultant for and is an advisory board member/unpaid consultant for Clovis. F.Y. Feng is an employee/paid consultant for Clovis, Janssen, Sanofi, Astellas, Bayer, and Genentech, and is an advisory board member/unpaid consultant for PFS Genomics. A.D. Simmons, M. Dowson, and S.P. Watkins are employees/paid consultants for and hold ownership interest (including patents) in Clovis. A. Loehr, D. Despain,

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Comment

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