Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, Villejuif, France.
Janssen Research and Development, Los Angeles, CA, USA.
Lancet Oncol. 2019 May;20(5):686-700. doi: 10.1016/S1470-2045(19)30082-8. Epub 2019 Apr 12.
In the interim analyses of the LATITUDE study, the addition of abiraterone acetate plus prednisone to androgen deprivation therapy (ADT) led to a significant improvement in overall survival and radiographic progression-free survival compared with placebos plus ADT in men with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (mCSPC). Here, we present long-term survival outcomes and safety of abiraterone acetate plus prednisone and ADT from the final analysis of the LATITUDE study.
This is a multicentre, randomised, double-blind, phase 3 trial done at 235 sites in 34 countries. Eligible patients (men aged ≥18 years) had newly diagnosed, histologically or cytologically confirmed prostate cancer with metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and at least two of the three high-risk prognostic factors (Gleason score of ≥8, presence of three or more lesions on bone scan, or presence of measurable visceral metastasis except lymph node metastasis). Patients were randomly assigned (1:1) to receive abiraterone acetate (1000 mg) once daily orally plus prednisone (5 mg) once daily orally and ADT (abiraterone acetate plus prednisone group) or matching placebos plus ADT (placebo group); each treatment cycle was 28 days. Randomisation was done by a centralised interactive web response system in a country-by-country scheme using permuted block randomisation, stratified by presence of visceral disease and ECOG performance status. The coprimary endpoint of overall survival was assessed in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT01715285 and is complete.
Between Feb 12, 2013, and Dec 11, 2014, 1209 patients were screened, of whom ten were ineligible because of study site violations. 1199 patients were randomly assigned to either the abiraterone acetate plus prednisone group (n=597) or placebo group (n=602). After the results of the first interim analysis (cutoff date Oct 31, 2016), the study was unmasked to patients and investigators, and patients in the placebo group were allowed to cross over to receive abiraterone acetate and prednisone plus ADT treatment as per a protocol amendment (Feb 15, 2017) in an open-label extension phase of the study (up to 18 months from the protocol amendment). This final analysis (data cutoff Aug 15, 2018) was done after a median follow-up of 51·8 months (IQR 47·2-57·0) and 618 deaths (275 [46%] of 597 in the abiraterone acetate plus prednisone group and 343 [57%] of 602 in the placebo group). Overall survival was significantly longer in the abiraterone acetate plus prednisone group (median 53·3 months [95% CI 48·2-not reached]) than in the placebo group (36·5 months [33·5-40·0]), with a hazard ratio of 0·66 (95% CI 0·56-0·78; p<0·0001). The most common grade 3-4 adverse events were hypertension (125 [21%] in the abiraterone acetate plus prednisone group vs 60 [10%] in the placebo group vs three [4%] in the 72 patients who crossed over from placebo to abiraterone acetate plus prednisone) and hypokalaemia (70 [12%] vs ten [2%] vs two [3%]). Serious adverse events of any grade occurred in 192 (32%) of 597 patients in the abiraterone acetate plus prednisone group, 151 (25%) of 602 in the placebo group, and four (6%) of 72 in the crossover group. The most common treatment-related serious adverse event was hypokalaemia (four [1%] patients in the abiraterone acetate plus prednisone group and none in the other groups). Treatment-related deaths occurred in three (<1%) patients each in the abiraterone acetate plus prednisone group (gastric ulcer perforation, sudden death, and cerebrovascular accident) and the placebo group (sudden death, cerebrovascular accident, and pneumonia), with none in the crossover group.
The combination of abiraterone acetate plus prednisone with ADT was associated with significantly longer overall survival than placebos plus ADT in men with newly diagnosed high-risk mCSPC and had a manageable safety profile. These findings support the use of abiraterone acetate plus prednisone as a standard of care in patients with high-risk mCSPC.
Janssen Research & Development.
在 LATITUDE 研究的中期分析中，与安慰剂加 ADT 相比，醋酸阿比特龙加泼尼松联合雄激素剥夺治疗（ADT）可显著改善新诊断的高危转移性去势敏感前列腺癌（mCSPC）男性的总生存和影像学无进展生存期。在此，我们报告 LATITUDE 研究最终分析中醋酸阿比特龙加泼尼松和 ADT 的长期生存结果和安全性。
这是一项在 34 个国家的 235 个地点进行的多中心、随机、双盲、III 期临床试验。符合条件的患者（年龄≥18 岁的男性）患有新诊断的、组织学或细胞学证实的伴转移的前列腺癌，东部合作肿瘤学组（ECOG）表现状态为 0-2，并且至少有三个高风险预后因素中的两个（Gleason 评分≥8、骨扫描上有三个或更多病变，或除淋巴结转移外有可测量的内脏转移）。患者按 1:1 随机分配接受醋酸阿比特龙（1000mg）每日一次口服联合泼尼松（5mg）每日一次口服和 ADT（醋酸阿比特龙加泼尼松组）或匹配安慰剂加 ADT（安慰剂组）；每个治疗周期为 28 天。随机化通过中央交互式网络响应系统以国家为单位按方案进行，采用置换块随机化，分层考虑内脏疾病和 ECOG 表现状态。总生存的主要终点在意向治疗人群中进行评估。这项研究在 ClinicalTrials.gov 上注册，编号为 NCT01715285，已经完成。
2013 年 2 月 12 日至 2014 年 12 月 11 日期间，有 1209 名患者接受了筛选，其中 10 名因研究地点违规而不合格。1199 名患者被随机分配到醋酸阿比特龙加泼尼松组（n=597）或安慰剂组（n=602）。第一次中期分析（截止日期为 2016 年 10 月 31 日）的结果公布后，该研究对患者和研究者进行了揭盲，并根据一项方案修正案（2017 年 2 月 15 日）允许安慰剂组的患者交叉接受醋酸阿比特龙和泼尼松加 ADT 治疗（自方案修正案起最多 18 个月）。这是在中位随访 51.8 个月（IQR 47.2-57.0）和 618 例死亡（醋酸阿比特龙加泼尼松组 275 [46%]，安慰剂组 343 [57%]）后进行的最终分析（数据截止日期为 2018 年 8 月 15 日）。与安慰剂组（中位 36.5 个月[33.5-40.0]）相比，醋酸阿比特龙加泼尼松组的总生存明显延长（中位 53.3 个月[48.2-未达到]），风险比为 0.66（95%CI 0.56-0.78；p<0.0001）。最常见的 3-4 级不良事件是高血压（醋酸阿比特龙加泼尼松组 125 [21%] vs 安慰剂组 60 [10%] vs 安慰剂组交叉到醋酸阿比特龙加泼尼松组的 72 名患者中的 3 [4%]）和低钾血症（醋酸阿比特龙加泼尼松组 70 [12%] vs 安慰剂组 10 [2%] vs 安慰剂组交叉到醋酸阿比特龙加泼尼松组的 72 名患者中的 2 [3%]）。醋酸阿比特龙加泼尼松组 597 名患者中有 192 名（32%）和安慰剂组 602 名患者中有 151 名（25%）发生任何等级的严重不良事件，而安慰剂组交叉到醋酸阿比特龙加泼尼松组的 72 名患者中有 4 名（6%）发生严重不良事件。最常见的与治疗相关的严重不良事件是低钾血症（醋酸阿比特龙加泼尼松组 4 名[1%]患者和其他组均无）。醋酸阿比特龙加泼尼松组各有 3 名（<1%）患者和安慰剂组各有 1 名（<1%）患者发生治疗相关死亡（醋酸阿比特龙加泼尼松组分别为胃溃疡穿孔、猝死和脑血管意外，安慰剂组分别为猝死、脑血管意外和肺炎），安慰剂组交叉到醋酸阿比特龙加泼尼松组的患者均无死亡。
与安慰剂加 ADT 相比，醋酸阿比特龙加泼尼松联合 ADT 可显著延长新诊断的高危转移性去势敏感前列腺癌男性的总生存，且安全性可管理。这些发现支持在高危 mCSPC 患者中使用醋酸阿比特龙加泼尼松作为标准治疗。
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