@article{c621c22e6666421dbf14465689b1c9e9,
title = "Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide",
abstract = "Background: Mutations in the androgen receptor (AR) ligand-binding domain (LBD), such as F877L and T878A, have been associated with resistance to next-generation AR-directed therapies. ARN-509-001 was a phase I/II study that evaluated apalutamide activity in castration-resistant prostate cancer (CRPC). Here, we evaluated the type and frequency of 11 relevant AR-LBD mutations in apalutamide-treated CRPC patients. Patients and methods: Blood samples from men with nonmetastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC) pre- or post-abiraterone acetate and prednisone (AAP) treatment (≥6 months' exposure) were evaluated at baseline and disease progression in trial ARN-509-001. Mutations were detected in circulating tumor DNA using a digital polymerase chain reaction-based method known as BEAMing (beads, emulsification, amplification and magnetics) (Sysmex Inostics' GmbH). Results: Of the 97 total patients, 51 had nmCRPC, 25 had AAP-na{\"i}ve mCRPC, and 21 had post-AAP mCRPC. Ninety-three were assessable for the mutation analysis at baseline and 82 of the 93 at progression. The overall frequency of detected AR mutations at baseline was 7/93 (7.5%) and at progression was 6/82 (7.3%). Three of the 82 (3.7%) mCRPC patients (2 AAP-na{\"i}ve and 1 post-AAP) acquired AR F877L during apalutamide treatment. At baseline, 3 of the 93 (3.2%) post-AAP patients had detectable AR T878A, which was lost after apalutamide treatment in 1 patient who continued apalutamide treatment for 12 months. Conclusions: The overall frequency of detected mutations at baseline (7.5%) and progression (7.3%) using the sensitive BEAMing assay was low, suggesting that, based on this assay, AR-LBD mutations such as F877L and T878A are not common contributors to de novo or acquired resistance to apalutamide.",
keywords = "ARN-509, Androgen receptor, Apalutamide, Castration-resistant prostate cancer, Mutations",
author = "Rathkopf, {Dana E.} and Smith, {M. R.} and Ryan, {C. J.} and Berry, {W. R.} and Shore, {N. D.} and G. Liu and Higano, {C. S.} and Alumkal, {J. J.} and R. Hauke and Tutrone, {R. F.} and M. Saleh and Maneval, {E. Chow} and S. Thomas and Ricci, {D. S.} and Yu, {M. K.} and {de Boer}, {C. J.} and A. Trinh and T. Kheoh and R. Bandekar and Scher, {H. I.} and Antonarakis, {E. S.}",
note = "Funding Information: This study was funded by Aragon Pharmaceuticals, Inc. Janssen Research & Development, LLC, is performing work on behalf of Aragon. No grant number is applicable. Dr. Rathkopf and Dr. Scher received support through the NIH/NCI Cancer Center Support Grant P30 CA008748. Funding Information: DER reports a consultant or advisory role at Janssen Oncology and research funding from Janssen Oncology, Medivation, Celgene, Takeda, Millennium, Ferring and Novartis; MRS reports a consultant role at Janssen Research & Development; CJR reports a consultant or advisory role at Bayer and Millennium; honoraria from Janssen Oncology and Astellas Pharma; and research funding from BIND Biosciences, Karyopharm Therapeutics and Novartis; WRB reports research grants from AHRQ; NDS reports a consultant or advisory role at Astellas Pharma, Bayer, Janssen Scientific Affairs, Dendreon, Sanofi, Takeda, Tolmar and Ferring; GL and MS have declared no conflicts of interest; CSH reports consulting fees or honoraria from AbbVie, Algeta, Astellas, Bayer, Dendreon, Genentech, Johnson & Johnson, Medivation, Novartis, Pfizer and Veridex; grants or research support from Amgen, Aragon Pharmaceuticals, AstraZeneca, Bayer, Dendreon, Exelixis, Genentech, Johnson & Johnson, Medivation, Millennium, Novartis, OncoGenex, Sanofi-Aventis US, Taxynergy and Teva; and other financial benefit from Cell Therapeutics; JJA reports institutional research funding from Aragon Pharmaceuticals, Janssen Oncology, Astellas Pharma, Millenium, Novartis and Zenith Epigenetics; income for consulting with Astellas Pharma and for educational sessions with Bayer HealthCare Pharmaceuticals; RJH reports stock ownership in Aethlon; honoraria from Best Doctors, Inc.; research funding from US Oncology, Bavarian Nordic, Bristol-Myers Squibb, Merck and Amgen; remuneration for an ABIM Subspecialty Board; and has a patent pending on an immunotherapeutic agent; RFT reports a consultant or advisory role at Medivation/Astellas; stock ownership in Nymox and Sophiris Bio Inc.; honoraria from Nymox; research funding from Nymox, Medivation/Astellas, Janssen Oncology, Sophiris Bio Inc., Bayer, American Medical Systems, Boston Scientific, Advaxis, MDxHealth and Genomic Health; and has served on speakers{\textquoteright} bureaus for Medivation/Astellas and Dendreon; ECM reports employment at Aragon Pharmaceuticals (past); ST, DSR, MKY, AT, TK and RB report employment at Janssen Research & Development and stock ownership in Johnson & Johnson; CJdB reports employment at Janssen Biologics and stock ownership in Johnson & Johnson; HIS reports institutional research funding from Exelixis, Innocrin, Medivation, Janssen, Aragon Pharmaceuticals, and Illumina; a consultant or advisory role at Astellas, Sanofi, Millenium, and WCG Oncology (compensated), and at Medivation, Janssen, and Aragon Pharmaceuticals (uncompensated); and receipt of travel, accommodations, and expenses from Astellas, Janssen, Millenium, and Sanofi; ESA reports a consultant or advisory role at Sanofi, Dendreon, Medivation, Janssen Biotech, ESSA and Astellas Pharma; honoraria from Sanofi, Dendreon, Medivation, Janssen Biotech, ESSA and Astellas Pharma; research funding from Janssen Biotech, Johnson & Johnson, Sanofi, Dendreon, Aragon Pharmaceuticals, Exelixis, Millennium, Genentech, Novartis, Astellas Pharma and Tokai Pharmaceuticals; and receipt of travel, accommodations and expenses from Sanofi, Dendreon and Medivation. Publisher Copyright: {\textcopyright} The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.",
year = "2017",
month = sep,
doi = "10.1093/annonc/mdx283",
language = "English (US)",
volume = "28",
pages = "2264--2271",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "Oxford University Press",
number = "9",
}