Health-related quality of life, pain, and symptomatic skeletal events with [177Lu]Lu-PSMA-617 in patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): an open-label, randomised, phase 3 trial.

Here, we present in-depth analyses of time to worsening of health-related quality of life (HRQOL) and pain, and time to first symptomatic skeletal events.

在这里，我们提供了对健康相关生活质量（HRQOL）和疼痛恶化时间以及首次症状性骨事件时间的深入分析。

Methods

PSMAfore, an open-label, randomised, phase 3 trial, was conducted at 74 investigator sites (including hospitals with nuclear medicine departments and the research facilities where patients were recruited) across 14 countries.

PSMAfore是一项开放标签、随机、III期试验，在14个国家的74个研究者站点（包括设有核医学部门的医院和招募患者的研究所）进行。

Eligible patients had metastatic castration-resistant prostate cancer, were candidates for ARPI change after one progression on a previous ARPI, had at least one PSMA-positive and no exclusionary PSMA-negative metastatic lesions by gallium-68 [68Ga]Ga-PSMA-11 PET-CT, were aged 18 years or older, and had an Eastern Cooperative Oncology Group performance status of 0-1.

符合条件的患者患有转移性去势抵抗性前列腺癌，是经过一次先前雄激素受体蛋白抑制剂（ARPI）进展后的ARPI变更候选人，至少有一个通过68Ga-PSMA-11 PET-CT检查为PSMA阳性的转移性病灶，没有排除性的PSMA阴性转移性病灶，年龄在18岁或以上，且东部肿瘤协作组（ECOG）表现状态为0-1级。

Patients were randomly assigned (1:1) to [177Lu]Lu-PSMA-617 (7·4 GBq; every 6 weeks for six cycles) or ARPI change (oral abiraterone or enzalutamide per local labelling).

患者被随机分配（1:1）至[177Lu]Lu-PSMA-617（7.4 GBq；每6周一次，共六个周期）或ARPI变更（根据当地标签口服阿比特龙或恩杂鲁胺）。

The primary endpoint was radiographic progression-free survival. Secondary endpoints included time to worsening in self-reported HRQOL (assessed using the Functional Assessment of Cancer Therapy-Prostate [FACT-P] and EQ-5D-5L) and pain (assessed using the Brief Pain Inventory-Short Form [BPI-SF]) and time to the first symptomatic skeletal event.

主要终点是影像学无进展生存期。次要终点包括自我报告的健康相关生活质量（使用癌症治疗功能评估-前列腺[FACT-P]和EQ-5D-5L评估）和疼痛（使用简短疼痛评估量表-短版[BPI-SF]评估）的恶化时间以及首次出现症状性骨事件的时间。

All analyses were done using the intention-to-treatprinciple.

所有分析均按照意向治疗原则进行。

The study met the primary endpoint of radiographic progression-free survival(reported previously), and overall survivalfollow-up is ongoing; present analyses are from the third interim analysis of overall survival. This trial is registered with ClinicalTrials.gov, NCT04689828.

该研究达到了放射学无进展生存期的主要终点（之前报告过），总生存随访正在进行中；目前的分析来自总生存的第三次中期分析。这项试验已在ClinicalTrials.gov注册，注册号为NCT04689828。

Results

Between June 15, 2021, and Oct 7, 2022, 468 patients (426 [91%] were White and 12 [3%] were Black or African American) were randomly assigned to [177Lu]Lu-PSMA-617 (n=234) or ARPI change (n=234).

在2021年6月15日至2022年10月7日期间，共有468名患者（其中426名[91%]为白人，12名[3%]为黑人或非裔美国人）被随机分配至[177Lu]Lu-PSMA-617组（n=234）或ARPI改变组（n=234）。

Median follow-up time from randomisation to the third interim analysis data cutoff date (Feb 27, 2024) was 24·11 months (IQR 20·24-27·60) in the [177Lu]Lu-PSMA-617 group and 24·13 months (20·24-27·37) in the ARPI change group.

从随机分组到第三次中期分析数据截止日期（2024年2月27日），[177Lu]Lu-PSMA-617组的中位随访时间为24.11个月（四分位数间距20.24-27.60），而ARPI改变组的中位随访时间为24.13个月（四分位数间距20.24-27.37）。

[177Lu]Lu-PSMA-617 delayed time to worsening in all assessed FACT-P, EQ-5D-5L, and BPI-SF scales and subscales versus ARPI change.

[177Lu]Lu-PSMA-617 延长了所有评估的 FACT-P、EQ-5D-5L 和 BPI-SF 量表及子量表的恶化时间，与 ARPI 变化相比。

In the [177Lu]Lu-PSMA-617 versus ARPI change groups, median time to worsening in FACT-P total score was 7·46 months (95% CI 6·08-8·54) versus 4·27 months (3·45-4·50; hazard ratio[HR] 0·61 [95% CI 0·50-0·75]), in EQ-5D-5L utility score was 6·28 months (4·70-7·89) versus 3·88 months (3·25-4·44; 0·67 [0·54-0·82]), and in BPI-SF pain intensity was 5·03 months (4·40-6·80) versus 3·65 months (3·09-4·37; 0·72 [0·59-0·88]).

在 [177Lu]Lu-PSMA-617 与 ARPI 变化组中，FACT-P 总分的恶化中位时间分别为 7.46 个月（95% 置信区间 6.08-8.54）与 4.27 个月（3.45-4.50；风险比 [HR] 0.61 [95% 置信区间 0.50-0.75]），EQ-5D-5L 效用分数的恶化中位时间为 6.28 个月（4.70-7.89）与 3.88 个月（3.25-4.44；0.67 [0.54-0.82]），BPI-SF 疼痛强度的恶化中位时间为 5.03 个月（4.40-6.80）与 3.65 个月（3.09-4.37；0.72 [0.59-0.88]）。

[177Lu]Lu-PSMA-617 also delayed symptomatic skeletal events versus ARPI change: median time to first symptomatic skeletal event was not reached (95% CI not estimable [NE]-NE) in the [177Lu]Lu-PSMA-617 group versus 17·97 months (14·26-NE) in the ARPI change group (HR 0·41 [0·26-0·63]).

[177Lu]Lu-PSMA-617还延迟了与ARPI变化相关的症状性骨骼事件：在[177Lu]Lu-PSMA-617组中，首次症状性骨骼事件的中位时间未达到（95%置信区间不可估计[NE]-NE），而在ARPI变化组中为17.97个月（14.26-NE）（风险比0.41 [0.26-0.63]）。

The most common grade 3 or worse treatment-emergent adverse eventwas anaemia (14 [6%] of 227 patients in the [177Lu]Lu-PSMA-617 group vs 16 [7%] of 232 patients in the ARPI change group).

最常见的3级或更严重的治疗相关不良事件是贫血（在[177Lu]Lu-PSMA-617组的227名患者中有14名[6%]，而在ARPI变化组的232名患者中有16名[7%]）。

There were no treatment-related deaths in the [177Lu]Lu-PSMA-617 group and one in the ARPI change group (cerebrovascular accident).

在[177Lu]Lu-PSMA-617组中没有治疗相关的死亡，而在ARPI变更组中有一例（脑血管意外）死亡。

interpretation

[177Lu]Lu-PSMA-617 might delay worsening of patient-reported outcomes and prevent symptomatic skeletal events versus ARPI change in taxane-naive patients with PSMA-positive metastatic castration-resistant prostate cancer whose disease has progressed once on a previous ARPI.

与ARPI变更相比，[177Lu]Lu-PSMA-617可能会延缓PSMA阳性转移性去势抵抗性前列腺癌患者的病情进展，这些患者在之前的ARPI治疗后疾病进展，且之前未接受过紫杉烷类化疗。

funding

Novartis.

诺华制药公司。