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-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.

Keywords: ARN-509; androgen receptor; apalutamide; castration-resistant prostate cancer; mutations.

Figure 1.

PSA changes in patients with androgen receptor F877L mutations detected at baseline [(A) Pt ID#1, (B) Pt ID#3] and at progression on apalutamide [(C) Pt ID#5, (D) Pt ID#4, (E) Pt ID#2]. AA, abiraterone acetate; PSA, prostate-specific antigen.

Figure 2.

PSA changes in patients with androgen receptor T878A mutations detected at baseline [(A) Pt ID#7, (B) Pt ID#8, (C) Pt ID#6] and at progression on apalutamide [(D) Pt ID#9]. AA, abiraterone acetate; PSA, prostate-specific antigen. Baseline characteristics for these patients are shown in Table 3.