: 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.
: Blood samples from men with non-metastatic 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).
Of the 97 total patients, 51 had nmCRPC, 25 had AAP-naïve mCRPC, and 21 had post-AAP mCRPC. Ninety-three were evaluable 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 82 (3.7%) mCRPC patients (two AAP-naïve and one post-AAP) acquired AR F877L during apalutamide treatment. At baseline, three of 93 (3.2%) post-AAP patients had detectable AR T878A, which was lost after apalutamide treatment in one patient who continued apalutamide treatment for 12 months.
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.
Annals of oncology : official journal of the European Society for Medical Oncology. 2017 Jun 15 [Epub ahead of print]
D 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, E S Antonarakis
Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York, USA., Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA., UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA., Cancer Centers of North Carolina, Raleigh, North Carolina, USA., Carolina Urologic Research Center, Myrtle Beach, South Carolina, USA., University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA., Nebraska Cancer Specialists, Omaha, Nebraska., Chesapeake Urologic Research Associates, Baltimore, Maryland, USA., University of Alabama Comprehensive Cancer Center, Birmingham, Alabama, USA., Aragon Pharmaceuticals, San Diego, California, USA., Janssen Research & Development, Spring House, Pennsylvania, USA., Janssen Research & Development, Los Angeles, California, USA., Janssen Biologics, B. V., Leiden, the Netherlands., Janssen Research & Development, San Diego, California, USA., Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland, USA.