University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan;
MD Anderson Cancer Center, Houston, Texas;
Clin Cancer Res. 2014 Aug 15;20(16):4218-27. doi: 10.1158/1078-0432.CCR-14-0356. Epub 2014 Jun 25.
Orteronel (TAK-700) is an investigational, nonsteroidal, oral, inhibitor of androgen synthesis with greater specificity for 17,20-lyase than for 17α-hydroxylase. We investigated orteronel without steroids in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC; M0).
Patients with nmCRPC and rising prostate-specific antigen (PSA) received orteronel 300 mg twice daily until PSA progression, metastases, or unacceptable toxicity. The primary endpoint was percentage of patients achieving PSA ≤0.2 ng/mL (undetectable levels) at 3 months. Secondary endpoints included safety, PSA response, time to metastases, and correlated endpoints.
Thirty-nine patients with a median baseline PSA doubling time of 2.4 months (range, 0.9-9.2) received a median of fourteen 28-day treatment cycles. PSA decreased >30% in 35 patients and 6 (16%) achieved PSA ≤ 0.2 ng/mL at 3 months. Median times to PSA progression and metastasis were 13.8 and 25.4 months, respectively. Kaplan-Meier estimates of freedom from PSA progression were 57% and 42% at 12 and 24 months, and of freedom from metastasis were 94% and 62% at 12 and 24 months, respectively. At 3 months, median testosterone declined by 89% from baseline. Adverse events led to therapy discontinuation in 12 patients and grade ≥3/4 adverse events occurred in 22 patients. Most frequent all-cause adverse events included fatigue (64%), hypertension (44%), diarrhea (38%), and nausea (33%), which were primarily grade 1/2.
Single-agent orteronel produced marked and durable declines in PSA in patients with nmCRPC. Orteronel has moderate but manageable toxicities and its chronic administration without steroids appears feasible.
Orteronel（TAK-700）是一种研究中的、非甾体类、口服雄激素合成抑制剂，对 17,20-裂合酶的特异性大于对 17α-羟化酶。我们在非转移性去势抵抗性前列腺癌（nmCRPC；M0）患者中研究了没有类固醇的 Orteronel。
nmCRPC 且 PSA 升高的患者接受 Orteronel 300mg，每日两次，直至 PSA 进展、转移或不可接受的毒性。主要终点是 3 个月时 PSA≤0.2ng/mL（无法检测到的水平）的患者比例。次要终点包括安全性、PSA 反应、转移时间和相关终点。
39 名患者的中位基线 PSA 倍增时间为 2.4 个月（范围为 0.9-9.2），接受了中位数为 14 个 28 天治疗周期。35 名患者的 PSA 下降>30%，6 名（16%）患者在 3 个月时 PSA≤0.2ng/mL。PSA 进展和转移的中位时间分别为 13.8 个月和 25.4 个月。Kaplan-Meier 估计的 PSA 无进展生存率分别为 57%和 42%，在 12 和 24 个月时，无转移生存率分别为 94%和 62%，在 12 和 24 个月时。在 3 个月时，与基线相比，睾酮中位数下降了 89%。12 名患者因治疗相关不良事件而停止治疗，22 名患者发生了≥3/4 级不良事件。最常见的全因不良事件包括疲劳（64%）、高血压（44%）、腹泻（38%）和恶心（33%），主要为 1/2 级。
单一药物 Orteronel 可使 nmCRPC 患者的 PSA 显著且持久下降。Orteronel 具有中等但可管理的毒性，其无类固醇的慢性给药似乎是可行的。
