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. Scher & 1 others Emmanuel 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

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Castration
Androgen Receptors
Prednisone
Prostatic Neoplasms
Mutation
Magnetics
Ligands
Therapeutics
Mutation Rate
Disease Progression
Abiraterone Acetate
Polymerase Chain Reaction
DNA
Neoplasms

Keywords

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

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide. / Rathkopf, Dana E.; 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.; Maneval, E. Chow; Thomas, S.; Ricci, D. S.; Yu, M. K.; de Boer, C. J.; Trinh, A.; Kheoh, T.; Bandekar, R.; Scher, H. I.; Antonarakis, Emmanuel.

In: Annals of Oncology, Vol. 28, No. 9, 2017, p. 2264-2271.

Research output: Contribution to journalArticle

Rathkopf, DE, Smith, MR, Ryan, CJ, Berry, WR, Shore, ND, Liu, G, Higano, CS, Alumkal, JJ, Hauke, R, Tutrone, RF, Saleh, M, Maneval, EC, Thomas, S, Ricci, DS, Yu, MK, de Boer, CJ, Trinh, A, Kheoh, T, Bandekar, R, Scher, HI & Antonarakis, E 2017, 'Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide', Annals of Oncology, vol. 28, no. 9, pp. 2264-2271. https://doi.org/10.1093/annonc/mdx283
Rathkopf, Dana E. ; 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. ; Maneval, E. Chow ; Thomas, S. ; Ricci, D. S. ; Yu, M. K. ; de Boer, C. J. ; Trinh, A. ; Kheoh, T. ; Bandekar, R. ; Scher, H. I. ; Antonarakis, Emmanuel. / Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide. In: Annals of Oncology. 2017 ; Vol. 28, No. 9. pp. 2264-2271.
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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 = "Androgen receptor, Apalutamide, ARN-509, 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 Emmanuel Antonarakis",
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TY - JOUR

T1 - Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide

AU - Rathkopf, Dana E.

AU - Smith, M. R.

AU - Ryan, C. J.

AU - Berry, W. R.

AU - Shore, N. D.

AU - Liu, G.

AU - Higano, C. S.

AU - Alumkal, J. J.

AU - Hauke, R.

AU - Tutrone, R. F.

AU - Saleh, M.

AU - Maneval, E. Chow

AU - Thomas, S.

AU - Ricci, D. S.

AU - Yu, M. K.

AU - de Boer, C. J.

AU - Trinh, A.

AU - Kheoh, T.

AU - Bandekar, R.

AU - Scher, H. I.

AU - Antonarakis, Emmanuel

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Androgen receptor

KW - Apalutamide

KW - ARN-509

KW - Castration-resistant prostate cancer

KW - Mutations

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U2 - 10.1093/annonc/mdx283

DO - 10.1093/annonc/mdx283

M3 - Article

VL - 28

SP - 2264

EP - 2271

JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

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ER -