Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer.
Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer.
复制标题
DOI：
10.1200/jco.2008.20.0642
复制
发表时间：
2009-08-10
期刊：
影响因子：
--
通讯作者：
de Bono JS
中科院分区：
文献类型：
--
作者：
Attard G;Reid AH;A'Hern R;Parker C;Oommen NB;Folkerd E;Messiou C;Molife LR;Maier G;Thompson E;Olmos D;Sinha R;Lee G;Dowsett M;Kaye SB;Dearnaley D;Kheoh T;Molina A;de Bono JS
据推测，去势抵抗性前列腺癌（CRPC）通常仍然依赖于激素。醋酸阿比特龙是一种有效的、选择性的、口服的 CYP17 抑制剂，CYP17 是雄激素和雌激素生物合成的关键酶。这是一项在去势、初治 CRPC 患者 (n = 54) 中进行醋酸阿比特龙的 I/II 期研究，II 期扩展为 1,000 mg (n = 42)，采用两阶段设计，如果超过 7 名患者的前列腺特异性抗原 (PSA) 下降 ≥ 50%，则拒绝零假设（零假设 = 0.1；备择假设 = 0.3；α = .05; β = .14)。每 12 周进行一次计算机断层扫描和循环肿瘤细胞 (CTC) 计数。通过添加地塞米松 0.5 mg/d 来抑制促肾上腺皮质激素和上游类固醇，以期逆转进展时的耐药性。 42 名 II 期患者中有 28 名 (67%) 观察到 PSA 下降 ≥ 50%，42 名患者中有 8 名 (19%) 观察到 PSA 下降 ≥ 90%。独立放射学评估报告称，24 名患有可测量疾病的 II 期患者中有 9 名 (37.5%) 出现部分缓解（实体瘤缓解评估标准）。还记录了 CTC 计数的减少。所有 II 期患者单独使用醋酸阿比特龙的 PSA 进展中位时间 (TTPP) 为 225 天（95% CI，162 至 287 天）。对所有 54 名 I/II 期患者进行了探索性分析；无论先前是否接受过地塞米松治疗，在疾病进展时添加地塞米松可逆转 33% 的患者的耐药性，并且治疗前的血清雄激素和雌二醇水平与醋酸阿比特龙和地塞米松治疗后 PSA 下降 ≥ 50% 和 TTPP 的概率相关。醋酸阿比特龙阻断 CYP17 导致 PSA 和 CTC 计数以及放射学反应下降，证实 CRPC 通常仍然是激素驱动的。
It has been postulated that castration-resistant prostate cancer (CRPC) commonly remains hormone dependent. Abiraterone acetate is a potent, selective, and orally available inhibitor of CYP17, the key enzyme in androgen and estrogen biosynthesis. This was a phase I/II study of abiraterone acetate in castrate, chemotherapy-naive CRPC patients (n = 54) with phase II expansion at 1,000 mg (n = 42) using a two-stage design to reject the null hypothesis if more than seven patients had a prostate-specific antigen (PSA) decline of ≥ 50% (null hypothesis = 0.1; alternative hypothesis = 0.3; α = .05; β = .14). Computed tomography scans every 12 weeks and circulating tumor cell (CTC) enumeration were performed. Prospective reversal of resistance at progression by adding dexamethasone 0.5 mg/d to suppress adrenocorticotropic hormone and upstream steroids was pursued. A decline in PSA of ≥ 50% was observed in 28 (67%) of 42 phase II patients, and declines of ≥ 90% were observed in eight (19%) of 42 patients. Independent radiologic evaluation reported partial responses (Response Evaluation Criteria in Solid Tumors) in nine (37.5%) of 24 phase II patients with measurable disease. Decreases in CTC counts were also documented. The median time to PSA progression (TTPP) on abiraterone acetate alone for all phase II patients was 225 days (95% CI, 162 to 287 days). Exploratory analyses were performed on all 54 phase I/II patients; the addition of dexamethasone at disease progression reversed resistance in 33% of patients regardless of prior treatment with dexamethasone, and pretreatment serum androgen and estradiol levels were associated with a probability of ≥ 50% PSA decline and TTPP on abiraterone acetate and dexamethasone. CYP17 blockade by abiraterone acetate results in declines in PSA and CTC counts and radiologic responses, confirming that CRPC commonly remains hormone driven.