Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
Department of Medical Oncology, University of Kansas Cancer Center, Kansas, ISA.
Prostate. 2023 Dec;83(16):1602-1609. doi: 10.1002/pros.24618. Epub 2023 Aug 29.
Androgen receptor (AR) gene alterations, as detected by circulating tumor cell-free DNA (cfDNA) genomic profiling, have been shown to emerge after a variable duration of androgen signaling inhibition. AR alterations were associated with inferior outcomes on treatment with androgen receptor pathway inhibitors (ARPI) in the first line metastatic castration-resistant prostate cancer (mCRPC) setting in a phase 2 trial. Here in, we assessed the impact of these AR alterations on survival outcomes in a real-world patient population of mCRPC experiencing disease progression on an ARPI.
In this IRB-approved retrospective study, consecutively seen patients with a confirmed diagnosis of mCRPC, with disease progression on a treatment with ARPIs in the first line mCRPC setting, with no prior exposure to an ARPI in the castration sensitive setting, and with available cfDNA profiling from a CLIA certified laboratory were included. Patients were categorized based on AR status: wild-type (AR ) or alteration-positive (AR ). The objective was to correlate overall survival (OS) after disease progression on the first-line ARPI with the presence or absence of AR alterations. Kaplan-Meier and Cox Regression Tests were used as implemented in R-Studio (v.4.2).
A total of 137 mCRPC patients were eligible: 69 with AR versus 68 with AR . The median OS posttreatment with the first ARPI was significantly higher for AR than AR patients (30.1 vs. 15.2 mos; p < 0.001). Of 108 patients who received a subsequent line of therapy, 63 received an alternate ARPI (AR 39 vs. 24 AR ), while 20 received a taxane-based therapy (11 AR vs. 9 AR ). Among patients receiving an alternate ARPI, AR had numerically shorter OS (16.8 vs. 30.4 mos, p = 0.1). Among patients receiving taxane-based regimens, the OS was not significantly different between AR and AR (14.5 vs. 10.1 mos, p = 0.18).
In this real-world study, mCRPC patients with AR alterations on cfDNA had inferior OS after disease progression on the first ARPI, compared to those who did not, and may impact outcomes on a subsequent ARPI but not on subsequent taxane-based therapy received. By providing survival estimates for patients with or without AR alterations, our data may aid in patient counseling, prognostication, treatment decision, and for designing future clinical trials in this setting.
通过循环肿瘤细胞游离 DNA（cfDNA）基因组分析检测到的雄激素受体（AR）基因改变，在经过一段时间的雄激素信号抑制后出现。在一项 2 期临床试验中，一线转移性去势抵抗性前列腺癌（mCRPC）中，AR 改变与雄激素受体通路抑制剂（ARPI）治疗的不良结局相关。在这里，我们评估了这些 AR 改变对一线 mCRPC 中接受 ARPI 治疗后疾病进展的真实世界患者人群的生存结局的影响。
在这项经机构审查委员会批准的回顾性研究中，连续观察了具有 mCRPC 明确诊断、一线 mCRPC 中接受 ARPI 治疗后疾病进展、无先前在去势敏感环境中接受 ARPI 暴露且可从 CLIA 认证实验室获得 cfDNA 分析的患者。患者根据 AR 状态进行分类：野生型（AR ）或改变阳性（AR ）。目的是将一线 ARPI 治疗后疾病进展的总生存（OS）与 AR 改变的存在或不存在相关联。Kaplan-Meier 和 Cox 回归检验如在 R-Studio（v.4.2）中实现的那样使用。
共有 137 名 mCRPC 患者符合条件：69 名 AR 与 68 名 AR 。接受一线 ARPI 治疗后，AR 患者的 OS 明显高于 AR 患者（30.1 与 15.2 mos；p<0.001）。在 108 名接受后续治疗的患者中，63 名接受了替代 ARPI（AR 39 与 24 AR ），而 20 名接受了紫杉烷类治疗（11 AR 与 9 AR ）。在接受替代 ARPI 的患者中，AR 的 OS 有缩短的趋势（16.8 与 30.4 mos，p=0.1）。在接受紫杉烷类方案的患者中，AR 和 AR 的 OS 无显著差异（14.5 与 10.1 mos，p=0.18）。
在这项真实世界研究中，cfDNA 中存在 AR 改变的 mCRPC 患者在一线 ARPI 治疗后疾病进展时 OS 较差，与未发生改变的患者相比，这可能会影响后续 ARPI 的结局，但不会影响后续接受的紫杉烷类治疗。通过为有或没有 AR 改变的患者提供生存估计，我们的数据可能有助于患者咨询、预后、治疗决策，并为该环境中的未来临床试验设计提供参考。
