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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide
D E Rathkopf1, M R Smith2, C J Ryan3
1Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York.
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.
Insights
Androgen receptor (AR) ligand-binding domain (LBD) mutations like F877L and T878A are not common causes of resistance to apalutamide in castration-resistant prostate cancer (CRPC). A sensitive BEAMing assay showed low mutation frequencies at baseline and progression.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Androgen receptor (AR) ligand-binding domain (LBD) mutations, including F877L and T878A, are linked to resistance against advanced AR-targeted therapies.
- The ARN-509-001 trial assessed apalutamide's efficacy in castration-resistant prostate cancer (CRPC).
- This study investigated the prevalence and types of 11 AR-LBD mutations in CRPC patients undergoing apalutamide treatment.
Purpose of the Study:
- To determine the frequency and types of specific AR-LBD mutations in patients with CRPC treated with apalutamide.
- To assess the role of AR-LBD mutations in de novo or acquired resistance to apalutamide therapy.
Main Methods:
- Blood samples were collected from patients with nonmetastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC) in the ARN-509-001 trial.
- Samples were analyzed at baseline and disease progression using the BEAMing (beads, emulsification, amplification and magnetics) assay for circulating tumor DNA.
- The assay detected 11 relevant AR-LBD mutations, including F877L and T878A.
Main Results:
- Of 97 patients, 93 were assessable at baseline and 82 at progression.
- The overall frequency of AR mutations was 7.5% at baseline and 7.3% at progression.
- AR F877L mutations were acquired by 3.7% of mCRPC patients during apalutamide treatment. AR T878A mutations were detected at baseline in 3.2% of post-AAP patients and were lost in one patient after apalutamide treatment.
Conclusions:
- The sensitive BEAMing assay revealed a low overall frequency of AR-LBD mutations (7.5% at baseline, 7.3% at progression).
- AR-LBD mutations like F877L and T878A do not appear to be common drivers of de novo or acquired resistance to apalutamide in CRPC.
- These findings suggest apalutamide maintains efficacy in a broader CRPC population than previously assumed based on mutation status.
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