Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York.
Massachusetts General Hospital and Harvard Medical School, Boston.
Ann Oncol. 2017 Sep 1;28(9):2264-2271. doi: 10.1093/annonc/mdx283.
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 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).
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.
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.
雄激素受体（AR）配体结合域（LBD）的突变，如 F877L 和 T878A，与对下一代 AR 靶向治疗的耐药性有关。ARN-509-001 是一项评估阿帕鲁胺在去势抵抗性前列腺癌（CRPC）中的活性的 I/II 期研究。在这里，我们评估了在接受阿帕鲁胺治疗的 CRPC 患者中 11 种相关 AR-LBD 突变的类型和频率。
在试验 ARN-509-001 中，评估了接受非转移性 CRPC（nmCRPC）和转移性 CRPC（mCRPC）预处理或预处理后（≥6 个月暴露）阿比特龙和泼尼松（AAP）治疗的男性的血液样本。使用基于数字聚合酶链反应的 BEAMing（珠子、乳化、扩增和磁性）（Sysmex Inostics 的 GmbH）方法在循环肿瘤 DNA 中检测突变。
在 97 名总患者中，51 名患有 nmCRPC，25 名患有 AAP 初治 mCRPC，21 名患有 AAP 后 mCRPC。93 名患者可用于基线和 82 名患者用于进展期的突变分析。基线时检测到 AR 突变的总体频率为 7/93（7.5%），进展时为 6/82（7.3%）。3 名 mCRPC 患者（2 名 AAP 初治和 1 名 AAP 后）在接受阿帕鲁胺治疗期间获得了 AR F877L。基线时，3 名（3.2%）接受 AAP 治疗的 AAP 后患者可检测到 AR T878A，其中 1 名患者在继续接受阿帕鲁胺治疗 12 个月后，该患者在接受阿帕鲁胺治疗后丢失了 AR T878A。
使用敏感的 BEAMing 检测，基线（7.5%）和进展（7.3%）时检测到的突变总频率较低，表明根据该检测，AR-LBD 突变，如 F877L 和 T878A，不是对阿帕鲁胺产生新发或获得性耐药的常见原因。
临床试验.gov 标识符：NCT01171898。
