Aglatimagene besadenovec (CAN-2409) with radiotherapy for patients with localised prostate cancer: a phase 3, multicentre, randomised, double-blind, placebo-controlled trial.

Previous studies with aglatimagene besadenovec (CAN-2409, hereafter referred to as aglatimagene) showed synergy with radiation and immune-mediated cytotoxicity in patients with prostate cancer.

先前的研究显示，与辐射联合使用时，aglatimagene besadenovec (CAN-2409，以下简称aglatimagene)在前列腺癌患者中显示出协同作用和免疫介导的细胞毒性。

We aimed to assess whether addition of aglatimagene plus prodrug (valacyclovir) to standard-of-care external beam radiation therapy (EBRT) could improve disease-free survival in this population.

我们旨在评估在标准治疗的外照射放疗（EBRT）中加入aglatimagene加前药（瓦拉西洛韦）是否能改善这一人群的无病生存期。

Methods

We conducted a phase 3, randomised, double-blind, placebo-controlledtrial at 51 medical centres (26 community and 25 institutional or military) across the USA and Puerto Rico in patients with intermediate or high-risk prostate cancer.

我们在美国和波多黎各的51个医疗中心（26个社区和25个机构或军事）进行了这项针对中高危前列腺癌患者的III期、随机、双盲、安慰剂对照试验。

Patients aged at least 18 years who were planning to undergo EBRT and with an Eastern Cooperative Oncology Group score of 0-2 were eligible.

年龄至少18岁的患者，计划接受外照射放疗（EBRT），且东部肿瘤协作组（Eastern Cooperative Oncology Group）评分在0-2分之间者符合入选条件。

Patients were randomly assigned (2:1) via central block-randomisation to receive either three courses of intraprostatic aglatimagene (5 × 1011 viral particles) plus valacyclovir or placebo plus valacyclovir, with randomisation stratified by risk category and androgen deprivation therapy (ADT) use.

患者通过中央分层随机分组（2:1）接受三种疗程的前列腺内注射aglatimagene（5 × 10^11病毒颗粒）加伐昔洛韦或安慰剂加伐昔洛韦治疗，随机分组根据风险类别和雄激素剥夺治疗（ADT）使用进行分层。

Patients received standard-of-care EBRT (78 Gy in 2 Gy fractions) or hypofractionated EBRT (60 Gy in 3 Gy fractions or 70 Gy in 2·5 Gy fractions) with optional ADT.

患者接受了标准的外照射放疗（78 Gy，每次2 Gy，共39次）或低分割外照射放疗（60 Gy，每次3 Gy，共20次或70 Gy，每次2.5 Gy，共28次），并可选择性地接受雄激素剥夺治疗（ADT）。

The primary endpoint was disease-free survival, defined as time-from-randomisation to prostate cancer recurrence or death in the intent-to-treat population (all randomly assigned patients).

主要终点是无病生存期，定义为从随机化到前列腺癌复发或死亡的时间，在意向治疗人群中（所有随机分配的患者）。

Safety was assessed in all individuals who received at least one injection.

所有至少接受过一次注射的个体均进行了安全性评估。

The trial is registered at ClinicalTrials.gov, NCT01436968, and long-term follow-up is ongoing.

该试验已在ClinicalTrials.gov注册，注册号为NCT01436968，且长期随访正在进行中。

Results

Between Feb 21, 2012, and Sept 9, 2021, 745 men (591 [79%] White, 121 [16%] Black) were randomly assigned to receive aglatimagene plus valacyclovir (n=496) or placebo plus valacyclovir (n=249).

在2012年2月21日至2021年9月9日期间，共有745名男性患者（591名[79%]为白人，121名[16%]为黑人）被随机分配接受aglatimagene加valacyclovir治疗（n=496）或安慰剂加valacyclovir治疗（n=249）。

After a median follow-up of 50·3 months (IQR 35·2-63·3), median disease-free survival was not reached (95% CI 121·78 to not reached) in the aglatimagene plus valacyclovir group versus 86·1 (IQR 29·7-143·0) months in the placebo plus valacyclovir group (hazard ratio0·70, 95% CI 0·52-0·94; p=0·016).

经过中位随访50.3个月（四分位数间距35.2-63.3个月），aglatimagene加valacyclovir组的中位无病生存期未达到（95%置信区间121.78至未达到），而安慰剂加valacyclovir组为86.1个月（四分位数间距29.7-143.0个月）（风险比0.70，95%置信区间0.52-0.94；p=0.016）。

Treatment-emergent adverse events (TEAEs) of grade 3 or worse occurred in 40 (8%) of 479 patients in the aglatimagene group and 17 (7%)of 232 patients in the placebo group.

治疗相关不良事件（TEAEs）中，3级或更严重的不良事件在479名aglatimagene组患者中有40例（8%），在232名安慰剂组患者中有17例（7%）。

The most common TEAE of grade 3 or worse was acute kidney injury in both the aglatimagene group (nine [2%] of 479 patients) and the placebo group (four [2%] of 232 patients).

最常见的3级或更严重的TEAE是急性肾损伤，在aglatimagene组有9例（2%）患者出现，在安慰剂组有4例（2%）患者出现。

Serious adverse events occurred in 28 (6%) of 479 patients in the aglatimagene group and 17 (7%) of 232 in the placebo group.

在479名接受aglatimagene治疗的患者中，有28名（6%）发生了严重不良事件；而在232名接受安慰剂治疗的患者中，有17名（7%）发生了严重不良事件。

Treatment-related serious adverse events occurred in eight (2%) patients in the aglatimagene group (four acute kidney injury, two pyrexia, and one each influenza-like symptoms and urinary retention) and five (2%) in the placebo group (four acute kidney injury, and one each increased creatinine levels and skin rash; one patient reported two serious adverse events).

在479名接受aglatimagene治疗的患者中，有8名（2%）发生了与治疗相关的严重不良事件（其中4名急性肾损伤，2名发热，各1名流感样症状和尿潴留）；而在232名接受安慰剂治疗的患者中，有5名（2%）发生了与治疗相关的严重不良事件（其中4名急性肾损伤，各1名肌酐水平升高和皮疹；有一名患者报告了两种严重不良事件）。

No treatment-related deaths were reported.

未报告与治疗相关的死亡事件。

interpretation

Aglatimagene plus valacyclovir was associated with longer disease-free survival than placebo plus valacyclovir when added to standard of radiotherapy for the treatment of localised prostate cancer, offering a meaningful benefit without increasing clinically significant toxicity.

在局部前列腺癌的治疗中，与安慰剂加更昔洛韦相比，阿格拉蒂马根加更昔洛韦联合标准放疗可实现更长的无病生存期，且在不增加临床显著毒性的情况下提供了显著的益处。

funding

Candel Therapeutics and US National Institutes of Health.

Candel治疗公司和美国国家卫生研究院