Attard Gerhardt, Reid Alison H M, A'Hern Roger, Parker Christopher, Oommen Nikhil Babu, Folkerd Elizabeth, Messiou Christina, Molife L Rhoda, Maier Gal, Thompson Emilda, Olmos David, Sinha Rajesh, Lee Gloria, Dowsett Mitch, Kaye Stan B, Dearnaley David, Kheoh Thian, Molina Arturo, de Bono Johann S
Royal Marsden National Health Service Foundation Trust, Sutton, Surrey, United Kingdom.
J Clin Oncol. 2009 Aug 10;27(23):3742-8. doi: 10.1200/JCO.2008.20.0642. Epub 2009 May 26.
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 > or = 50% (null hypothesis = 0.1; alternative hypothesis = 0.3; alpha = .05; beta = .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 > or = 50% was observed in 28 (67%) of 42 phase II patients, and declines of > or = 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 > or = 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.
据推测，去势抵抗性前列腺癌（CRPC）通常仍依赖激素。醋酸阿比特龙是一种强效、选择性且口服可用的CYP17抑制剂，CYP17是雄激素和雌激素生物合成中的关键酶。
这是一项针对去势、未接受过化疗的CRPC患者（n = 54）的醋酸阿比特龙I/II期研究，II期扩展至1000 mg（n = 42），采用两阶段设计，若超过7例患者的前列腺特异性抗原（PSA）下降≥50%，则拒绝原假设（原假设 = 0.1；备择假设 = 0.3；α = 0.05；β = 0.14）。每12周进行计算机断层扫描，并进行循环肿瘤细胞（CTC）计数。通过添加0.5 mg/d地塞米松以抑制促肾上腺皮质激素和上游类固醇，在疾病进展时进行前瞻性耐药逆转。
42例II期患者中有28例（67%）观察到PSA下降≥50%，42例患者中有8例（19%）观察到下降≥90%。独立影像学评估报告，在24例有可测量疾病的II期患者中有9例（37.5%）出现部分缓解（实体瘤疗效评价标准）。CTC计数也有下降记录。所有II期患者单独使用醋酸阿比特龙时，PSA进展的中位时间（TTPP）为225天（95%CI，162至287天）。对所有54例I/II期患者进行了探索性分析；疾病进展时添加地塞米松使33%的患者耐药逆转，无论之前是否接受过地塞米松治疗，治疗前血清雄激素和雌二醇水平与使用醋酸阿比特龙和地塞米松时PSA下降≥50%的概率以及TTPP相关。
醋酸阿比特龙对CYP17的阻断导致PSA和CTC计数下降以及影像学反应，证实CRPC通常仍由激素驱动。
