Pain and health-related quality-of-life outcomes with darolutamide in metastatic hormone-sensitive prostate cancer (ARANOTE): secondary and exploratory analyses of a multicentre, randomised, placebo-controlled, phase 3 trial.

In addition to survival, symptom control and health-related quality of life (HRQoL) are important factors in treatment decision making; we therefore report pain, HRQoL, and safety outcomes from the ARANOTE trial.

除了生存期外，症状控制和健康相关生活质量（HRQoL）是治疗决策中的重要因素；因此，我们报告了ARANOTE试验中的疼痛、HRQoL和安全性结果。

Methods

ARANOTE is an international, randomised, double-blind, placebo-controlled, phase 3 trial involving men aged 18 years or older, with Eastern Cooperative Oncology Group performance status 0-2 and recurrent or de novo mHSPC, treated at 133 cancer centres in 15 countries.

ARANOTE 是一项国际、随机、双盲、安慰剂对照的 III 期试验，涉及年龄在 18 岁或以上的男性患者，这些患者的东部肿瘤协作组（ECOG）表现状态为 0-2，且患有复发性或新发的转移性激素敏感性前列腺癌（mHSPC），在 15 个国家的 133 家癌症中心接受治疗。

Participants were randomly assigned (2:1) to 600 mg darolutamide or matching placebo orally twice daily, both with investigator's choice of androgen deprivation therapy (ADT; luteinising hormone-releasing hormone agonist or antagonist, or orchiectomy) starting within 12 weeks before randomisation.

参与者被随机分配（2:1）接受每日两次口服 600 mg 达罗他胺或匹配的安慰剂，均与研究者选择的雄激素剥夺治疗（ADT；促黄体生成激素释放激素激动剂或拮抗剂，或睾丸切除术）同时进行，ADT 在随机分组前 12 周内开始。

Randomisation was stratified by presence versus absence of visceral metastases and by previous versus no previous local therapy.

随机分组是根据有无内脏转移和之前是否接受过局部治疗进行分层的。

Treatment was assigned centrally using an interactive web response system based on a computer-generated permuted block randomisation list with block sizes of six.

治疗是通过交互式网络响应系统根据计算机生成的随机排列列表进行分配的，排列块大小为六。

The investigators, the participants, and the sponsor remained masked to treatment assignment throughout the study.

在整个研究期间，研究者、参与者和赞助商对治疗分配保持盲态。

The primary endpoint (reported previously) was radiological progression-free survival. Here, we assessed time to pain progression (≥2-point increase in Brief Pain Inventory-Short Form worst pain score or initiation of opioid for ≥7 days; secondary endpoint) and time to deterioration of overall wellbeing (≥10-point decrease in Functional Assessment of Cancer Therapy-Prostate [FACT-P] total score; prespecified exploratory endpoint).

主要终点（之前已报告）是无放射学进展的生存期。在这里，我们评估了疼痛进展的时间（简短形式最痛评分增加≥2分或开始使用阿片类药物≥7天；次要终点）和整体福祉恶化的时长（功能性癌症治疗-前列腺[FACT-P]总分降低≥10分；预先设定的探索性终点）。

Pain and HRQoL outcomes were analysed in the intention to treat population; safety was analysed in all treated patients according to treatment actually received.

在意向治疗人群中分析了疼痛和健康相关生活质量（HRQoL）的结果；根据实际接受的治疗，对所有接受治疗的患者进行了安全性分析。

The trial, registered at ClinicalTrials.gov, NCT04736199, is ongoing, but no longer recruiting.

该试验已在ClinicalTrials.gov注册，注册号为NCT04736199，目前正在进行中，但已不再招募新患者。

Results

Between Feb 23, 2021, and June 14, 2022, 669 patients (all male; 376 [56%] White, 209 [31%] Asian, 65 [10%] Black, 19 [3%] other race) were randomly assigned to receive darolutamide (n=446) or placebo (n=223).

2021年2月23日至2022年6月14日期间，共有669名患者（全部为男性；376名[56%]白人，209名[31%]亚洲人，65名[10%]黑人，19名[3%]其他种族）被随机分配接受达罗他胺（n=446）或安慰剂（n=223）。

At the data cutoff date for the primary analysis (June 7, 2024), the median follow-up duration for the analyses presented here was 22·8 months (IQR 12·3-27·4) in the darolutamide group and 20·3 months (11·4-25·2) in the placebo group.

在2024年6月7日主要分析的数据截止日期，本研究中呈现的分析的中位随访时间在达罗他胺组为22.8个月（四分位数间距12.3-27.4），在安慰剂组为20.3个月（四分位数间距11.4-25.2）。

Darolutamide delayed time to pain progression (HR 0·72; 95% CI 0·54-0·96) and extended time to deterioration in FACT-P total score (HR 0·76; 0·61-0·94) versus placebo.

达罗他胺延迟了疼痛进展的时间（HR 0·72; 95% CI 0·54-0·96）并延长了FACT-P总分恶化的时间（HR 0·76; 0·61-0·94）与安慰剂相比。

The most common grade 3-4 adverse events were hypertension (19 [4%] of 445 patients who received darolutamide vs eight [4%] of 221 patients who received placebo), anaemia (14 [3%] vs eight [4%]), and aspartate aminotransferase increase (ten [2%] vs one [<1%]).

最常见的3-4级不良事件是高血压（445名接受达罗他胺治疗的患者中有19例[4%]，而接受安慰剂治疗的221名患者中有8例[4%]），贫血（14例[3%]对8例[4%]），以及天冬氨酸氨基转移酶升高（10例[2%]对1例[<1%]）。

Serious adverse events occurred in 105 (24%) versus 52 (24%) patients, respectively.

严重不良事件分别发生在105名（24%）和52名（24%）患者中。

One treatment-related grade 5 event occurred, reported as death (not otherwise specified).

发生了一起与治疗相关的5级事件，报告为死亡（未具体说明）。

interpretation

Along with the known survival benefits, the clinically meaningful delays in pain progression and time to deterioration of overall wellbeing support consideration of darolutamide plus ADT as a standard-of-care treatment option in patients with mHSPC.

除了已知的生存益处外，疼痛进展和总体健康状况恶化的临床意义延迟支持将达罗他胺加雄激素剥夺治疗（ADT）作为转移性激素敏感性前列腺癌（mHSPC）患者的标准治疗选择。

funding

Bayer and Orion Pharma.

拜耳和奥利安制药。