Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide. Academic Article uri icon

Overview

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. CLINICALTRIALS.GOV IDENTIFIER: NCT01171898.

authors

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

publication date

  • September 1, 2017

Research

keywords

  • Androgen Antagonists
  • Point Mutation
  • Prostatic Neoplasms, Castration-Resistant
  • Receptors, Androgen
  • Thiohydantoins

Identity

PubMed Central ID

  • PMC5834046

Scopus Document Identifier

  • 85029875339

Digital Object Identifier (DOI)

  • 10.1093/annonc/mdx283

PubMed ID

  • 28633425

Additional Document Info

volume

  • 28

issue

  • 9