Abemaciclib plus abiraterone in patients with metastatic castration-resistant prostate cancer (CYCLONE 2): a randomised, double-blind, placebo-controlled, phase 3 trial.

We aimed to evaluate the safety and efficacy of abemaciclib in combination with abiraterone in patients with mCRPC.

我们旨在评估阿贝西利与阿比特龙联合使用在mCRPC患者中的安全性和有效性。

Methods

CYCLONE 2 was a randomised, double-blind, placebo-controlled, phase 3 study done in 89 hospitals and academic and private research centres in 12 countries.

CYCLONE 2 是一项在12个国家的89家医院、学术和私立研究中心进行的随机、双盲、安慰剂对照的III期研究。

All study parts had identical eligibility criteria, and used block randomisation with the same stratification factors (previous docetaxel treatment, presence of measurable disease, and type of progression).

所有研究部分都有相同的资格标准，并使用了相同的分层因素（之前的多西他赛治疗、可测量疾病的出现以及疾病进展的类型）进行分块随机化。

Participants were adults aged 18 years and older with histologically confirmed adenocarcinoma of the prostate and metastatic disease as documented by bone scans, CT scans, or MRI scans, and radiographic or PSA progression during continuous androgen deprivation therapy.

参与者为18岁及以上的成年人，经组织学证实为前列腺腺癌，并通过骨扫描、CT扫描或MRI扫描以及在持续雄激素剥夺治疗期间的放射学或PSA进展证实有转移性疾病。

Previous docetaxel for metastatic castration-sensitive prostate cancer was permitted; previous abiraterone, apalutamide, enzalutamide, darolutamide, or CDK4 and CDK6 inhibitors were exclusionary.

允许之前接受过针对转移性去势敏感性前列腺癌的多西他赛治疗；之前接受过阿比特龙、阿帕鲁胺、恩杂鲁胺、达鲁他胺或CDK4和CDK6抑制剂治疗的患者则被排除在外。

The trial was conducted in three parts.

该试验分为三个部分进行。

Part 1 was a four-arm, placebo-controlledsafety and dose-finding lead-in to determine the recommended phase 2 dose of abemaciclib with abiraterone.

第一部分是一个四项的、安慰剂对照的安全性和剂量探索性初步研究，旨在确定阿贝西利与阿比特龙联合使用的推荐第二阶段剂量。

Participants were randomly assigned (2:2:1:1) to receive abiraterone (1000 mg orally once daily) and prednisone or prednisolone (5 mg orally twice daily) with either abemaciclib at 150 mg or 200 mg orally twice daily or with matching placebo (150 mg or 200 mg twice daily).

参与者被随机分配（2:2:1:1）接受阿比特龙（每日一次口服1000毫克）和泼尼松或泼尼松龙（每日两次口服5毫克），同时分别接受阿贝西利150毫克或200毫克每日两次口服或匹配的安慰剂（150毫克或200毫克每日两次）。

In part 2 and part 3, patients were randomly assigned (1:1) to standard abiraterone and prednisone or prednisolone plus either abemaciclib at the recommended phase 2 dose or matching placebo.

在第2部分和第3部分，患者被随机分配（1:1）接受标准阿比特龙和泼尼松或泼尼松龙，加上推荐的第2阶段剂量的阿贝西利或匹配的安慰剂。

Patients, investigators, and sponsor were masked to treatment assignment.

患者、研究者和赞助商对治疗分配情况均不知情。

The primary outcome, investigator-assessed radiographic progression-free survival, was analysed in the intention-to-treat(participants from all study parts) population.

主要结果指标，即研究者评估的影像学无进展生存期，在意向治疗（所有研究部分的参与者）人群中进行了分析。

Patients who received at least one dose of abiraterone, abemaciclib, or placebo were included in the safety population.

纳入安全性人群的患者是那些至少接受过一次阿比特龙、阿贝西利或安慰剂治疗的患者。

This trial is registered at ClinicalTrials.gov, NCT03706365, and is completed.

该试验已在ClinicalTrials.gov注册，注册号为NCT03706365，并已完成。

Results

Between Nov 26, 2018, and July 20, 2022, 515 patients were screened for eligibility, 393 of whom were randomly assigned, 206 patients to abemaciclib plus abiraterone and 187 to placebo plus abiraterone.

2018年11月26日至2022年7月20日期间，共有515名患者进行了资格筛查，其中393名患者被随机分配，206名患者接受阿贝西利联合阿比特龙治疗，187名患者接受安慰剂联合阿比特龙治疗。

The median age was 70·0 years (IQR 63·0-76·0). 289 (74%) of 393 patients identified as White, 80 (20%) as Asian, 17 (4%) as Black or African American, and seven (2%) as multiple race or not reported.

中位年龄为70.0岁（四分位数间距63.0-76.0岁）。在393名患者中，有289名（74%）被识别为白人，80名（20%）为亚洲人，17名（4%）为黑人或非裔美国人，7名（2%）为多种族或未报告。

The highest tested dose of 200 mg abemaciclib administered twice daily was chosen as the recommended phase 2 dose.

选择每日两次200 mg阿贝西利作为推荐的二期剂量。

The median follow-up time was 26·3 months (IQR 22·1-48·2) for the abemaciclib plus abiraterone group and 25·6 months (22·1-40·8) for the placebo plus abiraterone group.

阿贝西利联合阿比特龙组的中位随访时间为26.3个月（四分位数间距22.1-48.2），而安慰剂联合阿比特龙组的中位随访时间为25.6个月（四分位数间距22.1-40.8）。

The primary endpoint of radiographic progression-free survivalwas not met: radiographic progression-free survivalevents were reported in 92 (45%) of 206 patients in the abemaciclib plus abiraterone group and 95 (51%) of 187 patients in the placebo plus abiraterone group (HR 0·83 [95% CI 0·62-1·11]; p=0·21).

影像学无进展生存期的主要终点未达到：在206名接受阿贝西利联合阿比特龙治疗的患者中，有92例（45%）报告了影像学无进展生存期事件，而在187名接受安慰剂联合阿比特龙治疗的患者中，有95例（51%）报告了影像学无进展生存期事件（HR 0·83 [95% 置信区间 0·62-1·11]；p=0·21）。

Median radiographic progression-free survivalwas 22·0 months (95% CI 19·3-27·5) for abemaciclib plus abiraterone and 20·3 months (16·5-24·4) for placebo plus abiraterone.

中位影像学无进展生存期为阿贝西利联合阿比特龙组22.0个月（95% 置信区间 19.3-27.5），安慰剂联合阿比特龙组为20.3个月（16.5-24.4）。

The most common grade 3 or higher adverse events reported in the abemaciclib plus abiraterone group were anaemia (28 [14%] of 206 vs eight [4%] of 185 in the placebo plus abiraterone group), neutropenia (26 [13%] vs one [1%]), and alanine aminotransferase increase (18 [9%] vs 12 [6%]).

在阿贝西利联合阿比特龙组中，报告的最常见3级或更高级别的不良事件是贫血（206例中有28例[14%]，而安慰剂联合阿比特龙组的185例中有八例[4%]）、中性粒细胞减少症（26例[13%]对一例[1%]）和丙氨酸氨基转移酶升高（18例[9%]对12例[6%]）。

Serious adverse events occurred in 91 (44%) of 206 patients in the abemaciclib plus abiraterone group and in 68 (37%) of 185 patients in the placebo plus abiraterone group.

在阿贝西利联合阿比特龙组中，有91例（44%）的206名患者出现了严重不良事件，而在安慰剂联合阿比特龙组的185名患者中有68例（37%）出现了严重不良事件。

There were three treatment-related deaths due to interstitial lung disease in the abemaciclib plus abiraterone group.

在阿贝西利加阿比特龙组中，有三例与治疗相关的死亡是由于间质性肺病导致的。

interpretation

Dual inhibition of CDK4 and CDK6 and the androgen receptor pathway with abemaciclib plus abiraterone did not improve radiographic progression-free survivalcompared with abiraterone alone in the CYCLONE 2 study population with mCRPC.

在CYCLONE 2研究中，对于转移性去势抵抗性前列腺癌（mCRPC）患者，阿贝西利联合阿比特龙双重抑制CDK4和CDK6以及雄激素受体通路，并没有改善与单独使用阿比特龙相比的影像学无进展生存期。

Safety of the combination was consistent with the previously reported safety of the individual drugs.

该组合的安全性与其单药先前报告的安全性一致。

Additional research is required to identify effective combination therapies for patients with mCRPC, especially in those presenting with adverse prognostic characteristics.

需要进一步的研究来确定转移性去势抵抗性前列腺癌（mCRPC）患者的有效联合治疗方案，特别是在那些具有不良预后特征的患者中。

funding

Eli Lilly.

礼来制药