Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide

Dana E. Rathkopf, M. R. Smith, C. J. Ryan, W. R. Berry, N. D. Shore, G. Liu, C. S. Higano, J. J. Alumkal, R. Hauke, R. F. Tutrone, M. Saleh, E. Chow Maneval, S. Thomas, D. S. Ricci, M. K. Yu, C. J. de Boer, A. Trinh, T. Kheoh, R. Bandekar, H. I. ScherE. S. Antonarakis

Research output: Contribution to journalArticle

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-naïve 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-naïve 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.

Original languageEnglish (US)
Pages (from-to)2264-2271
Number of pages8
JournalAnnals of Oncology
Volume28
Issue number9
DOIs
StatePublished - 2017

Keywords

  • ARN-509
  • Androgen receptor
  • Apalutamide
  • Castration-resistant prostate cancer
  • Mutations

ASJC Scopus subject areas

  • Hematology
  • Oncology

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