Nivolumab plus docetaxel versus placebo plus docetaxel for androgen receptor pathway inhibitor-pretreated and chemotherapy-naive metastatic castration-resistant prostate cancer (CheckMate 7DX): a double-blind, randomised, phase 3 trial.

We aimed to assess the efficacy and safety of adding nivolumab to docetaxel versus docetaxel alone in ARPI-pretreated, chemotherapy-naive mCRPC.

我们旨在评估在ARPI预处理、化疗前的mCRPC中，将nivolumab加入多西他赛与单独使用多西他赛相比的疗效和安全性。

Methods

CheckMate 7DX was a double-blind, randomised, phase 3 trial that enrolled adult patients (aged ≥18 years) with histologically confirmed, ARPI-pretreated, and chemotherapy-naive mCRPC at 291 hospitals and cancer centres across 27 countries.

CheckMate 7DX 是一项双盲、随机、III期试验，在27个国家的291家医院和癌症中心招募了成年患者（年龄≥18岁），这些患者具有组织学证实的、经过雄激素受体通路抑制剂（ARPI）治疗的、且未接受过化疗的转移性去势抵抗性前列腺癌（mCRPC）。

Patients had documented progression within 6 months of screening and an Eastern Cooperative Oncology Group performance status of 0 or 1.

患者在筛选前6个月内有明确的疾病进展，并且东部肿瘤协作组（Eastern Cooperative Oncology Group）的体能状态评分为0或1。

Patients were randomly assigned (1:1) to nivolumab (360 mg), or equivalent placebo, and docetaxel (75 mg/m2) intravenously every 3 weeks for up to ten doses, followed by nivolumab (480 mg) or equivalent placebo every 4 weeks.

患者被随机分配（1:1）接受纳武利尤单抗（360 mg）或等效安慰剂，并静脉注射多西他赛（75 mg/m2），每3周一次，最多十次剂量，随后每4周一次接受纳武利尤单抗（480 mg）或等效安慰剂。

Randomisation, stratified by previous ARPI therapy and visceral disease, was done using interactive response technology in permuted blocks with a block size of six.

随机分组，根据先前的ARPI治疗和内脏疾病进行分层，使用交互式响应技术进行分层区组随机化，区组大小为六。

Patients, investigators, and the trial sponsor were masked to individual patient treatment assignment.

患者、研究者和试验赞助商对个别患者的治疗分配情况均不知情。

The primary endpoints were radiographic progression-free survivalby blinded independent central review and overall survival, assessed in all randomly assigned patients.

主要终点是通过盲法独立中央审查的影像学无进展生存和总生存，这些指标在所有随机分配的患者中进行评估。

Safety was assessed in all patients who received at least one dose of study drug.

所有接受至少一剂研究药物的患者均进行了安全性评估。

This study is registered with ClinicalTrials.gov, NCT04100018, and is completed.

该研究已在ClinicalTrials.gov注册，注册号为NCT04100018，并已完成。

Results

Between March 11, 2020, and Aug 2, 2022, 1414 patients were screened for eligibility, 1030 of whom were randomly assigned to nivolumab plus docetaxel (n=514) or placebo plus docetaxel (n=516).

2020年3月11日至2022年8月2日期间，共有1414名患者被筛查以确定其是否符合入选标准，其中1030名患者被随机分配接受纳武利尤单抗加多西他赛(n=514)或安慰剂加多西他赛(n=516)治疗。

All participants were male, median age was 70 years (range 34-91), 662 (64%) were White, 240 (23%) were Asian, and 35 (3%) were Black or African American.

所有参与者均为男性，中位年龄为70岁（范围34-91岁），其中662人（64%）为白人，240人（23%）为亚洲人，35人（3%）为黑人或非裔美国人。

With a median follow-up of 17·2 months (IQR 13·2-22·0), median radiographic progression-free survivalwas 9·4 months (95% CI 8·5-10·3) in the nivolumab plus docetaxel group versus 8·7 months (95% CI 8·4-10·0) in the placebo plus docetaxel group (hazard ratio[HR] 0·96 [99% CI 0·77-1·19]; p=0·59) and median overall survivalwas 18·7 months (95% CI 17·0-21·0) versus 18·9 months (95% CI 17·3-22·0, HR 1·09 [99·41% CI 0·84-1·43]; p=0·36).

中位随访时间为17.2个月（四分位数间距13.2-22.0），在纳武利尤单抗联合多西他赛组中，中位影像学无进展生存期为9.4个月（95%置信区间8.5-10.3），而在安慰剂联合多西他赛组中为8.7个月（95%置信区间8.4-10.0，风险比[HR] 0.96 [99%置信区间0.77-1.19]；p=0.59），中位总生存期分别为18.7个月（95%置信区间17.0-21.0）和18.9个月（95%置信区间17.3-22.0，HR 1.09 [99.41%置信区间0.84-1.43]；p=0.36）。

Grade 3-4 treatment-related adverse events occurred in 223 (44%) of 510 patients in the nivolumab plus docetaxel group and 187 (37%) of 510 in the placebo plus docetaxel group.

在纳武利尤单抗联合多西他赛组中，510名患者中有223名（44%）发生了3-4级治疗相关不良事件，而在安慰剂联合多西他赛组中，510名患者中有187名（37%）发生了3-4级治疗相关不良事件。

The most common grade 3-4 events in both treatment groups were neutropenia (37 [7%] in the nivolumab plus docetaxel group and 50 [10%] in the placebo plus docetaxel group) and decreased neutrophil count (41 [8%] and 39 [8%]).

两组治疗中最常见的3-4级事件是中性粒细胞减少症（在纳武单抗联合多西他赛组中有37例[7%]，在安慰剂联合多西他赛组中有50例[10%]）和中性粒细胞计数减少（分别为41例[8%]和39例[8%]）。

Any-grade treatment-related serious adverse events occurred in 107 (21%) patients in the nivolumab plus docetaxel group and 77 (15%) in the placebo plus docetaxel group. 12 deaths were attributed to nivolumab plus docetaxel (three due to sepsis; one each due to Guillain-Barré syndrome, diverticulitis, myocarditis, liver injury, peritonitis, pneumonitis, pneumonia, and diarrhoea; and one due to unknown causes) and one was attributed to placebo plus docetaxel (due to pneumocystis).

任何级别的治疗相关严重不良事件在纳武单抗联合多西他赛组的107名患者（21%）和安慰剂联合多西他赛组的77名患者（15%）中发生。有12例死亡归因于纳武单抗联合多西他赛（其中三例因败血症；各有1例因吉兰-巴雷综合征、憩室炎、心肌炎、肝损伤、腹膜炎、肺炎、肺炎和腹泻；以及1例因未知原因），而有1例死亡归因于安慰剂联合多西他赛（因肺孢子虫病）。

interpretation

Nivolumab plus docetaxel did not improve progression-free survivalor overall survivalversus placebo plus docetaxel in patients with ARPI-pretreated, chemotherapy-naive mCRPC.

在ARPI预处理且化疗未经治疗的转移性去势抵抗性前列腺癌（mCRPC）患者中，Nivolumab联合多西他赛并未改善无进展生存期或总生存期，与安慰剂联合多西他赛相比。

These findings do not support the use of combinations of anti-PD-1 immune checkpoint inhibitors and docetaxel in the treatment of unselected populations of patients with ARPI-pretreated, chemotherapy-naive mCRPC.

这些发现不支持在未经选择的ARPI预处理且化疗未经治疗的mCRPC患者中使用抗PD-1免疫检查点抑制剂与多西他赛联合治疗。

funding

Bristol Myers Squibb.

百时美施贵宝公司