Geriatric Research, Education and Clinical Center (GRECC), U.S. Department of Veterans Affairs Puget Sound Health Care System, Seattle, Washington.
Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington.
Clin Cancer Res. 2021 Nov 1;27(21):6001-6011. doi: 10.1158/1078-0432.CCR-21-1819. Epub 2021 Aug 18.
In metastatic castration-resistant prostate cancer (mCRPC) low serum androgens prior to starting abiraterone acetate (AA) is associated with more rapid progression. We evaluated the effect of AA on androgens in castration-resistant prostate cancer (CRPC) metastases and associations of intratumoral androgens with response.
We performed a phase II study of AA plus prednisone in mCRPC. The primary outcome was tissue testosterone at 4 weeks. Exploratory outcomes were association of steroid levels and genomic alterations with response, and escalating AA to 2,000 mg at progression.
Twenty-nine of 30 men were evaluable. Testosterone in metastatic biopsies became undetectable at 4 weeks ( < 0.001). Serum and tissue dehydroepiandrosterone sulfate (DHEAS) remained detectable in many patients and was not increased at progression. Serum and tissue DHEAS in the lowest quartile (pretreatment), serum DHEAS in the lowest quartile (4 weeks), and undetectable tissue DHEAS (on-therapy) associated with rapid progression (20 vs. 48 weeks, = 0.0018; 20 vs. 52 weeks, = 0.0003; 14 vs. 40 weeks, = 0.0001; 20 vs. 56 weeks, = 0.02, respectively). One of 16 men escalating to 2,000 mg had a 30% PSA decline; 13 developed radiographic progression by 12 weeks. Among patients with high serum DHEAS at baseline, wild-type (WT) PTEN status associated with longer response (61 vs. 33 weeks, = 0.02).
Low-circulating adrenal androgen levels are strongly associated with an androgen-poor tumor microenvironment and with poor response to AA. Patients with CRPC with higher serum DHEAS levels may benefit from dual androgen receptor (AR)-pathway inhibition, while those in the lowest quartile may require combinations with non-AR-directed therapy.
在起始醋酸阿比特龙治疗前血清雄激素水平低与转移性去势抵抗性前列腺癌（mCRPC）进展更快相关。我们评估了醋酸阿比特龙（AA）对去势抵抗性前列腺癌（CRPC）转移患者雄激素的作用以及肿瘤内雄激素与反应的相关性。
我们进行了一项 AA 联合泼尼松治疗 mCRPC 的 II 期研究。主要结局是 4 周时组织中的睾酮水平。探索性结局是类固醇水平和基因组改变与反应的相关性，以及进展时 AA 增至 2000mg。
30 例患者中有 29 例可评估。转移性活检组织中的睾酮在 4 周时变得无法检测到（<0.001）。许多患者的血清和组织硫酸脱氢表雄酮（DHEAS）仍可检测到，且在进展时并未增加。最低四分位数的血清和组织 DHEAS（治疗前）、最低四分位数的血清 DHEAS（4 周时）和治疗期间不可检测的组织 DHEAS（on-therapy）与快速进展相关（20 与 48 周，=0.0018；20 与 52 周，=0.0003；14 与 40 周，=0.0001；20 与 56 周，=0.02）。16 例患者中有 1 例进展至 2000mg 时 PSA 下降 30%；13 例在 12 周时出现放射学进展。在基线时血清 DHEAS 较高的患者中，野生型（WT）PTEN 状态与较长的反应时间相关（61 与 33 周，=0.02）。
低循环肾上腺雄激素水平与雄激素贫乏的肿瘤微环境强烈相关，并与 AA 反应不良相关。血清 DHEAS 水平较高的 CRPC 患者可能受益于双重雄激素受体（AR）通路抑制，而处于最低四分位数的患者可能需要与非 AR 靶向治疗联合。
