Background

The majority of patients with metastatic castration-resistant prostate cancer (mCRPC) will have disease progression of a uniformly fatal disease. mCRPC is driven by both activated androgen receptors and elevated intratumoural androgens; however, the current standard of care is therapy that targets a single androgen signalling mechanism. We aimed to investigate the combination treatment using apalutamide plus abiraterone acetate, each of which suppresses the androgen signalling axis in a different way, versus standard care in mCRPC.

Methods

ACIS was a randomised, placebo-controlled, double-blind, phase 3 study done at 167 hospitals in 17 countries in the USA, Canada, Mexico, Europe, the Asia-Pacific region, Africa, and South America. We included chemotherapy-naive men (aged ≥18 years) with mCRPC who had not been previously treated with androgen biosynthesis signalling inhibitors and were receiving ongoing androgen deprivation therapy, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a Brief Pain Inventory-Short Form question 3 (ie, worst pain in the past 24 h) score of 3 or lower. Patients were randomly assigned (1:1) via a centralised interactive web response system with a permuted block randomisation scheme (block size 4) to oral apalutamide 240 mg once daily plus oral abiraterone acetate 1000 mg once daily and oral prednisone 5 mg twice daily (apalutamide plus abiraterone–prednisone group) or placebo plus abiraterone acetate and prednisone (abiraterone–prednisone group), in 28-day treatment cycles. Randomisation was stratified by presence or absence of visceral metastases, ECOG performance status, and geographical region. Patients, the investigators, study team, and the sponsor were masked to group assignments. An independent data-monitoring committee continually monitored data to ensure ongoing patient safety, and reviewed efficacy data. The primary endpoint was radiographic progression-free survival assessed in the intention-to-treat population. Safety was reported for all patients who received at least one dose of study drug. This study is completed and no longer recruiting and is registered with ClinicalTrials.gov, number NCT02257736.

Findings

982 men were enrolled and randomly assigned from Dec 10, 2014 to Aug 30, 2016 (492 to apalutamide plus abiraterone–prednisone; 490 to abiraterone–prednisone). At the primary analysis (median follow-up 25·7 months [IQR 23·0–28·9]), median radiographic progression-free survival was 22·6 months (95% CI 19·4–27·4) in the apalutamide plus abiraterone–prednisone group versus 16·6 months (13·9–19·3) in the abiraterone–prednisone group (hazard ratio [HR] 0·69, 95% CI 0·58–0·83; p<0·0001). At the updated analysis (final analysis for overall survival; median follow-up 54·8 months [IQR 51·5–58·4]), median radiographic progression-free survival was 24·0 months (95% CI 19·7–27·5) versus 16·6 months (13·9–19·3; HR 0·70, 95% CI 0·60–0·83; p<0·0001). The most common grade 3–4 treatment-emergent adverse event was hypertension (82 [17%] of 490 patients receiving apalutamide plus abiraterone–prednisone and 49 [10%] of 489 receiving abiraterone–prednisone). Serious treatment-emergent adverse events occurred in 195 (40%) patients receiving apalutamide plus abiraterone–prednisone and 181 (37%) patients receiving abiraterone–prednisone. Drug-related treatment-emergent adverse events with fatal outcomes occurred in three (1%) patients in the apalutamide plus abiraterone–prednisone group (2 pulmonary embolism, 1 cardiac failure) and five (1%) patients in the abiraterone–prednisone group (1 cardiac failure and 1 cardiac arrest, 1 mesenteric arterial occlusion, 1 seizure, and 1 sudden death).

Interpretation

Despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone–prednisone improved radiographic progression-free survival. Additional studies to identify subgroups of patients who might benefit the most from combination therapy are needed to further refine the treatment of mCRPC.

Funding

Janssen Research & Development.

中文翻译：

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阿帕鲁胺加醋酸阿比特龙和强的松对比安慰剂加阿比特龙和强的松治疗转移性去势抵抗性前列腺癌 (ACIS)：一项随机、安慰剂对照、双盲、多国、3 期研究

背景

大多数患有转移性去势抵抗性前列腺癌 (mCRPC) 的患者会出现均一致命疾病的疾病进展。mCRPC 由活化的雄激素受体和升高的瘤内雄激素驱动；然而，目前的护理标准是针对单一雄激素信号机制的治疗。我们的目的是研究使用阿帕鲁胺加醋酸阿比特龙的联合治疗，与 mCRPC 中的标准治疗相比，每一种都以不同的方式抑制雄激素信号轴。

方法

ACIS 是一项随机、安慰剂对照、双盲、3 期研究，在美国、加拿大、墨西哥、欧洲、亚太地区、非洲和南美洲的 17 个国家的 167 家医院进行。我们纳入了既往未接受过雄激素生物合成信号抑制剂治疗且正在接受持续雄激素剥夺治疗且东部肿瘤协作组 (ECOG) 体能状态为 0 或 1 的未接受过化疗的男性（年龄≥18 岁）和 mCRPC，以及简短疼痛量表-简表问题 3（即过去 24 小时内最严重的疼痛）得分为 3 或更低。患者被随机分配（1：1) 通过具有置换区组随机方案（区组大小 4）的集中式交互式网络响应系统，口服阿帕鲁胺 240 mg 每天一次加口服醋酸阿比特龙 1000 mg 每天一次和口服泼尼松 5 mg 每天两次（阿帕鲁胺加阿比特龙-泼尼松组）或安慰剂加醋酸阿比特龙和泼尼松（阿比特龙-泼尼松组），治疗周期为 28 天。根据是否存在内脏转移、ECOG 体能状态和地理区域对随机化进行分层。患者、研究人员、研究团队和申办者被蒙蔽到分组分配。一个独立的数据监测委员会持续监测数据以确保持续的患者安全，并审查疗效数据。主要终点是在意向治疗人群中评估的影像学无进展生存期。所有接受至少一剂研究药物的患者均报告了安全性。该研究已完成，不再招募，并在 ClinicalTrials.gov 注册，编号为 NCT02257736。

发现

从 2014 年 12 月 10 日至 2016 年 8 月 30 日，982 名男性被纳入并随机分配（492 名接受阿帕鲁胺加阿比特龙-泼尼松；490 名接受阿比特龙-泼尼松）。在初步分析中（中位随访 25·7 个月 [IQR 23·0–28·9]），中位影像学无进展生存期为 22·6 个月（95% CI 19·4–27·4）阿帕鲁胺加阿比特龙-泼尼松组对比阿比特龙-泼尼松组的 16·6 个月 (13·9-19·3)（风险比 [HR] 0·69，95% CI 0·58-0·83；p<0 ·0001)。在更新的分析中（总生存期的最终分析；中位随访 54·8 个月 [IQR 51·5–58·4]），中位影像学无进展生存期为 24·0 个月（95% CI 19·7– 27·5）与 16·6 个月（13·9–19·3；HR 0·70，95% CI 0·60–0·83；p<0·0001）。最常见的 3-4 级治疗出现的不良事件是高血压（接受阿帕鲁胺联合阿比特龙-泼尼松的 490 名患者中的 82 名 [17%] 和接受阿比特龙-泼尼松的 489 名患者中的 49 名 [10%]）。195 名 (40%) 接受阿帕鲁胺联合阿比特龙-泼尼松治疗的患者和 181 名 (37%) 接受阿比特龙-泼尼松治疗的患者发生了严重的治疗中出现的不良事件。阿帕鲁胺加阿比特龙-泼尼松组 3 例 (1%) 患者（2 例肺栓塞，1 例心力衰竭）和阿比特龙-泼尼松组 5 例 (1%) 患者发生了与药物相关的治疗相关不良事件和致命结局。 1 例心力衰竭和 1 例心脏骤停、1 例肠系膜动脉闭塞、1 例癫痫发作和 1 例猝死）。195 名 (40%) 接受阿帕鲁胺联合阿比特龙-泼尼松治疗的患者和 181 名 (37%) 接受阿比特龙-泼尼松治疗的患者发生了严重的治疗中出现的不良事件。阿帕鲁胺加阿比特龙-泼尼松组 3 例 (1%) 患者（2 例肺栓塞，1 例心力衰竭）和阿比特龙-泼尼松组 5 例 (1%) 患者发生了与药物相关的治疗相关不良事件和致命结局。 1 例心力衰竭和 1 例心脏骤停、1 例肠系膜动脉闭塞、1 例癫痫发作和 1 例猝死）。195 名 (40%) 接受阿帕鲁胺联合阿比特龙-泼尼松治疗的患者和 181 名 (37%) 接受阿比特龙-泼尼松治疗的患者发生了严重的治疗中出现的不良事件。阿帕鲁胺加阿比特龙-泼尼松组 3 例 (1%) 患者（2 例肺栓塞，1 例心力衰竭）和阿比特龙-泼尼松组 5 例 (1%) 患者发生了与药物相关的治疗相关不良事件和致命结局。 1 例心力衰竭和 1 例心脏骤停、1 例肠系膜动脉闭塞、1 例癫痫发作和 1 例猝死）。

解释

尽管使用了一种积极且成熟的疗法作为比较，阿帕鲁胺加阿比特龙-泼尼松改善了影像学无进展生存期。需要更多的研究来确定可能从联合治疗中获益最多的患者亚组，以进一步完善 mCRPC 的治疗。

资金

杨森研发。