Prognostic and predictive value of baseline PSMA-PET total tumour volume and SUVmean in metastatic castration-resistant prostate cancer in ENZA-p (ANZUP1901): a substudy from a multicentre, open-label, randomised, phase 2 trial.

Adding [177Lu]Lu-PSMA-617 to enzalutamide improved overall survivalcompared with enzalutamide in patients with metastatic castration-resistant prostate cancer in the ENZA-p trial. This prespecified substudy of ENZA-p evaluated baseline PSMA-PET quantitative parameters as predictive and prognostic biomarkers for enzalutamide plus [177Lu]Lu-PSMA-617 and enzalutamide monotherapy.

在ENZA-p试验中，将[177Lu]Lu-PSMA-617添加到恩杂鲁胺中，与单独使用恩杂鲁胺相比，改善了转移性去势抵抗性前列腺癌患者的总生存期。这项ENZA-p的预定亚研究评估了基线PSMA-PET定量参数作为恩杂鲁胺加[177Lu]Lu-PSMA-617和恩杂鲁胺单药治疗的预测和预后生物标志物。

Methods

ENZA-p was an open-label, randomised, phase 2 trial done in 15 hospitals in Australia.

ENZA-p 是一项在澳大利亚15家医院进行的开放标签、随机、二期试验。

Participants were aged 18 years or older with progressive metastatic castration-resistant prostate cancer who had not previously been treated with docetaxel or androgen receptor pathway inhibitors (abiraterone permitted) for metastatic castration-resistant prostate cancer, had [68Ga]Ga PSMA-PET-CT-positive disease, an Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide.

参与者年龄在18岁或以上，患有进展性转移性去势抵抗性前列腺癌，之前未接受过多西他赛或雄激素受体通路抑制剂（允许使用阿比特龙）治疗，具有[68Ga]Ga PSMA-PET-CT阳性病变，东部肿瘤协作组表现状态为0-2，以及至少有两项早期进展的危险因素。

Patients were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to either enzalutamide 160 mg daily (oral) or enzalutamide 160 mg daily plus adaptive-dosed (two or four doses) intravenous [177Lu]Lu-PSMA-617 7·5 GBq every 6-8 weeks.

患者通过中央化的基于网络的系统，使用带有随机成分的最小化方法按1:1的比例随机分配，接受每日口服恩杂鲁胺160毫克或每日口服恩杂鲁胺160毫克加上自适应剂量（两剂或四剂）的静脉注射[177Lu]Lu-PSMA-617 7.5 GBq，每6-8周一次。

The primary endpoint was prostate-specific antigen (PSA) progression-free survival, which has been reported previously.

主要终点是前列腺特异性抗原（PSA）无进展生存期，之前已经报告过。

All participants underwent baseline [68Ga]Ga-PSMA-11 PET-CT to assess eligibility (SUVmax >15 at a single site and SUVmax >10 at all larger tumour sites).

所有参与者都接受了基线[68Ga]Ga-PSMA-11 PET-CT扫描以评估资格（单个部位SUVmax>15，所有较大肿瘤部位SUVmax>10）。

PSMA-PET parameters were quantified with semi-automated software to derive PSMA-TTV and SUVmean and correlated with overall and PSA progression-free survivalin a prespecified analysis, with the primary endpoint of this substudy being overall survival. Thresholds were based on SUVmean highest quartile (Q4 vs Q1-3) and PSMA-TTV median at baseline.

使用半自动软件对PSMA-PET参数进行量化，以推导出PSMA-TTV和SUVmean，并与总生存和PSA无进展生存期进行相关性分析，在预先设定的分析中，本子研究的主要终点是总生存。阈值基于SUVmean最高四分位数（Q4 vs Q1-3）和基线时PSMA-TTV的中位数。

We used the Kaplan-Meier method and Cox regression models and analysed patients on a treatment received basis.

我们使用了Kaplan-Meier方法和Cox回归模型，并基于接受治疗的患者进行了分析。

The trial is registered with ClinicalTrials.gov, NCT04419402, and follow-up is complete.

该试验已在ClinicalTrials.gov注册，注册号为NCT04419402，随访已完成。

Results

Between Aug 17, 2020, and July 26, 2022, 162 participants were randomly assigned to enzalutamide (n=79) or enzalutamide plus [177Lu]Lu-PSMA-617 (n=83).

2020年8月17日至2022年7月26日期间，共有162名参与者被随机分配接受恩杂鲁胺(n=79)或恩杂鲁胺加[177Lu]Lu-PSMA-617(n=83)治疗。

This substudy included the 160 of the 162 randomly assigned patients who received study treatment (79 in the enzalutamide group and 81 in the enzalutamide plus [177Lu]Lu-PSMA-617 group).

这项子研究包括了162名随机分配的患者中的160名，这些患者接受了研究治疗（恩杂鲁胺组79名和恩杂鲁胺加[177Lu]Lu-PSMA-617组81名）。

Median follow-up at the final data cutoff (July 31, 2024) was 34 months (IQR 29-39), with 96 overall survivalevents (53 with enzalutamide and 43 with enzalutamide plus [177Lu]Lu-PSMA-617).

最终数据截止日期（2024年7月31日）的中位随访时间为34个月（四分位数间距29-39），共发生96例总生存事件（其中53例使用恩杂鲁胺，43例使用恩杂鲁胺加[177Lu]Lu-PSMA-617）。

Baseline median SUVmean was 7·7 (IQR 6·5-9·8) and median PSMA-TTV was 234 mL (76-687).

基线中位SUVmean为7.7（四分位数间距6.5-9.8），中位PSMA-TTV为234毫升（76-687）。

Median overall survivalfor PSMA-TTV below or above the median in the enzalutamide group was 39 months (95% CI 31-not estimable) versus 20 months (13-24; HR 0·23 [95% CI 0·13-0·42], log-rank p<0·0001).

在恩杂鲁胺组中，PSMA-TTV低于或高于中位数的患者的中位总生存期分别为39个月（95%置信区间31-不可估计）与20个月（13-24个月；风险比0.23 [95%置信区间0.13-0.42]，对数秩检验p<0.0001）。

The corresponding median overall survivalfor PSMA-TTV below or above the median in the enzalutamide plus [177Lu]Lu-PSMA-617 group was 35 months (95% CI 32-37) versus 28 months (26-34; HR 0·66 [0·36-1·21], log-rank p=0·18).

在恩杂鲁胺联合[177Lu]Lu-PSMA-617组中，PSMA-TTV低于或高于中位数的患者的中位总生存期分别为35个月（95%置信区间32-37个月）与28个月（26-34个月；风险比0.66 [0.36-1.21]，对数秩检验p=0.18）。

The test for interaction between PSMA-TTV and treatment group for overall survivalwas p=0·0078.

PSMA-TTV与治疗组对总生存的交互作用检验的p值为0.0078。

Median overall survivalfor SUVmean Q4 versus Q1-3 in the enzalutamide group was 29 months (95% CI 17-39) versus 25 months (21-31; HR 0·84 [0·44-1·60], log-rank p=0·59).

在恩杂鲁胺组中，SUVmean Q4与Q1-3的中位总生存期分别为29个月（95%置信区间17-39）和25个月（21-31；HR 0.84 [0.44-1.60]，对数秩检验p=0.59）。

For enzalutamide plus [177Lu]Lu-PSMA-617, median overall survivalfor SUVmean Q4 versus Q1-3 was 32 months (95% CI 21-not estimable) versus 34 months (27-35; HR 0·80 [0·38-1·68], log-rank p=0·56).

对于恩杂鲁胺联合[177Lu]Lu-PSMA-617治疗，SUVmean Q4组与Q1-3组的中位总生存期分别为32个月（95%置信区间21-未估算）和34个月（27-35个月；风险比0.80 [0.38-1.68]，Log-rank检验p=0.56）。

The test for interaction between SUVmean (Q4 vs Q1-3) and treatment group for overall survivalwas p=0·88.

SUVmean（Q4与Q1-3）与治疗组之间对总生存期的交互作用检验的p值为0.88。

interpretation

Baseline PSMA-TTV is prognostic for overall survivaland predictive for a beneficial effect on overall survivalwith the addition of [177Lu]Lu-PSMA-617 to enzalutamide as first-line treatment for high-risk metastatic castration-resistant prostate cancer.

基线PSMA-TTV对于总生存具有预后意义，并且在将[177Lu]Lu-PSMA-617作为高风险转移性去势抵抗性前列腺癌一线治疗添加到恩杂鲁胺时，对总生存有益效果具有预测性。

By contrast, PSMA SUVmean was not prognostic for PSA progression-free survivalor overall survivalwhen [177Lu]Lu-PSMA-617 was administered with enzalutamide.

相比之下，当[177Lu]Lu-PSMA-617与恩杂鲁胺联合使用时，PSMA SUVmean对于PSA无进展生存或总生存并不具有预后意义。

funding

The Prostate Cancer Research Alliance initiative (Movember and Australian Federal Government), Prostate Cancer Foundation Challenge Award, St Vincent's Clinic Foundation, GenesisCare, RoyMorgan, Endocyte (a Novartis company), and Astellas.

前列腺癌研究联盟倡议（Movember和澳大利亚联邦政府）、前列腺癌基金会挑战奖、圣文森特诊所基金会、GenesisCare、RoyMorgan、Endocyte（诺华公司的一个部门）以及Astellas。