Cabozantinib plus atezolizumab in metastatic prostate cancer (CONTACT-02): final analyses from a phase 3, open-label, randomised trial.

We aimed to assess efficacy and safety of cabozantinib, a tyrosine kinase inhibitor with immunomodulatory properties, plus the PD-L1 inhibitor atezolizumab in these patients.

我们旨在评估酪氨酸激酶抑制剂兼有免疫调节特性的cabozantinib与PD-L1抑制剂atezolizumab联合治疗这些患者的疗效和安全性。

Methods

CONTACT-02 is an open-label, randomised, phase 3 study that enrolled patients at 184 sites across 24 countries (in Europe, North America, Asia-Pacific, and Latin America).

CONTACT-02是一项开放标签、随机、III期研究，在24个国家的184个地点招募患者（包括欧洲、北美、亚太和拉丁美洲）。

Men aged 18 years and older, with an Eastern Cooperative Oncology Group performance status score of 0 or 1, and who had mCRPC and measurable extrapelvic soft-tissue metastases (lymph node or visceral) that had progressed on one previous ARPI were eligible.

年龄在18岁及以上的男性，东部肿瘤协作组（ECOG）表现状态评分为0或1，且患有转移性去势抵抗性前列腺癌（mCRPC），并有可测量的盆腔外软组织转移（淋巴结或内脏），在一种先前的雄激素受体途径抑制剂（ARPI）治疗后进展的患者符合入选条件。

Patients were randomly assigned 1:1 to cabozantinib (40 mg orally once daily) plus atezolizumab (1200 mg intravenously once every 3 weeks) or ARPI switch (abiraterone 1000 mg orally once-daily plus prednisone 5 mg orally twice-daily, or enzalutamide 160 mg orally once-daily) using a web-based interactive response technology system and stratified by the presence of liver metastasis, previous docetaxel therapy, and disease status at first ARPI initiation.

患者按1:1的比例随机分配至cabozantinib（每日口服40毫克）联合atezolizumab（每3周静脉注射1200毫克）组，或ARPI转换治疗组（abiraterone每日口服1000毫克加泼尼松每日两次口服5毫克，或enzalutamide每日口服160毫克），使用基于网络的交互式响应技术系统进行分组，并根据是否存在肝转移、之前是否接受过docetaxel治疗以及首次ARPI治疗时的疾病状态进行分层。

Dual primary endpoints were progression-free survivalin the first 400 randomly assigned patients (progression-free survivalintention-to treat [ITT] population) and overall survivalin all randomly assigned patients (ITT population).

双重主要终点是在前400名随机分配的患者中无进展生存期（无进展生存意向治疗[ITT]人群）和在所有随机分配的患者中总生存期（ITT人群）。

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

所有接受至少一剂研究治疗的患者均进行了安全性评估。

Although the study is ongoing, with some patients remaining in follow-up, this analysis represents the protocol-specified final analysis.

尽管研究仍在进行中，部分患者仍在随访中，但本次分析代表了协议规定的最终分析。

This trial is registered with ClinicalTrials.gov, NCT04446117.

该试验已在ClinicalTrials.gov注册，注册号为NCT04446117。

Results

Between Aug 20, 2020 and June 7, 2023, 575 patients were randomly assigned to cabozantinib plus atezolizumab (n=289) or ARPI switch (n=286).

在2020年8月20日至2023年6月7日期间，共有575名患者被随机分配接受卡博替尼联合阿替利珠单抗治疗（n=289）或ARPI转换治疗（n=286）。

Most patients were White (440 [77%]) or Asian (78 [14%]).

大多数患者为白人（440 [77%]）或亚洲人（78 [14%]）。

After a median follow-up of 11·8 months (IQR 9·9-19·3), cabozantinib plus atezolizumab significantly improved progression-free survivalversus ARPI switch (median 6·3 months [95% CI 6·2-8·8] vs 4·2 months [3·7-5·7]; hazard ratio[HR] 0·65 [95% CI 0·50-0·84], p=0·0007).

中位随访时间为11.8个月（四分位数间距9.9-19.3），与ARPI转换相比，卡博替尼联合阿替利珠单抗显著改善了无进展生存期（中位数6.3个月 [95% 置信区间 6.2-8.8] 对比 4.2个月 [3.7-5.7]；风险比[HR] 0.65 [95% 置信区间 0.50-0.84]，p=0.0007）。

After a median follow-up of 23·1 months (IQR 17·4-30·5), overall survivalwas not significantly different between the cabozantinib plus atezolizumab and ARPI switch groups (median 14·8 months [95% CI 13·4-16·7] vs 15·0 months [13·0-18·5]; HR 0·89 [95% CI 0·72-1·10], p=0·30).

中位随访时间为23.1个月（四分位数间距17.4-30.5），卡博佐替尼联合阿替利珠单抗组与ARPI转换组的总生存期没有显著差异（中位生存期分别为14.8个月[95%置信区间13.4-16.7]和15.0个月[13.0-18.5]；风险比为0.89[95%置信区间0.72-1.10]，p=0.30）。

Any-cause grade 3-4 adverse events occurred in 158 (56%) of 284 patients given cabozantinib plus atezolizumab and 74 (26%) of 284 patients given ARPI switch; the most common in the cabozantinib plus atezolizumab group were hypertension (24 [8%] of 284 patients) and anaemia (23 [8%]) and the most common in the ARPI switch group was anaemia (18 [6%] of 284 patients).

在给予卡博佐替尼联合阿替利珠单抗的284名患者中，有158名（56%）发生了3-4级的任何原因不良事件，而在给予ARPI转换的284名患者中，有74名（26%）发生了3-4级的任何原因不良事件；卡博佐替尼联合阿替利珠单抗组中最常见的不良事件是高血压（284名患者中的24名，占8%）和贫血（284名患者中的23名，占8%），而ARPI转换组中最常见的不良事件是贫血（284名患者中的18名，占6%）。

Serious adverse events deemed related to treatment occurred in 45 (16%) of 284 patients in the cabozantinib plus atezolizumab group and in 11 (4%) of 284 patients in the ARPI switch group; the most common with cabozantinib plus atezolizumab was diarrhoea (five [2%] of 284 patients) and the most common with ARPI switch was increase in alanine aminotransferase (two [1%] of 284 patients).

在284名接受卡博替尼联合阿替利珠单抗治疗的患者中，有45例（16%）发生了被认为与治疗相关的严重不良事件，在284名接受ARPI转换治疗的患者中，有11例（4%）发生了此类事件；卡博替尼联合阿替利珠单抗治疗中最常见的不良事件是腹泻（284名患者中有5例，占2%），而ARPI转换治疗中最常见的不良事件是丙氨酸氨基转移酶升高（284名患者中有2例，占1%）。

Adverse events of any cause led to discontinuation of all components of study treatment in 49 (17%) of 284 patients in the cabozantinib plus atezolizumab group and in 42 (15%) of 284 patients in the ARPI switch group.

任何原因导致的不良事件导致284名接受卡博替尼联合阿替利珠单抗治疗的患者中有49例（17%）停止了所有研究治疗的组成部分，在284名接受ARPI转换治疗的患者中，有42例（15%）发生了此类情况。

No treatment-related deaths occurred.

未发生与治疗相关的死亡事件。

interpretation

Cabozantinib plus atezolizumab, a novel drug combination that does not directly target androgen receptor signalling, could be a useful treatment option for patients with mCRPC and soft-tissue metastases who have progressed on an ARPI.

卡博替尼联合阿替利珠单抗是一种新型药物组合，不直接针对雄激素受体信号通路，对于那些在雄激素受体蛋白抑制剂（ARPI）治疗后进展的转移性去势抵抗性前列腺癌（mCRPC）患者，并伴有软组织转移的患者，可能是一个有用的治疗选择。

funding

Exelixis in partnership with Ipsen, Takeda, and Roche.

Exelixis与Ipsen、武田和罗氏合作。