背景:恩扎鲁胺和[177Lu]Lu-前列腺特异性膜抗原(PSMA)-617均可改善转移性去势抵抗性前列腺癌患者的总生存率。雄激素和PSMA受体具有密切的胞内关系,数据表明,如果同时靶向,则会有互补的益处。在这项研究中,我们评估了恩杂鲁胺联合适应性剂量[177Lu]Lu-PSMA-617与单独恩杂鲁胺作为转移性去势抵抗性前列腺癌一线治疗的活性和安全性.
方法:ENZA-p是开放标签,随机化,在澳大利亚15家医院进行的2期对照试验。参与者为18岁或以上患有转移性去势抵抗性前列腺癌的男性,此前未使用多西他赛或雄激素受体途径抑制剂治疗转移性去势抵抗性前列腺癌。镓-68[68Ga]Ga-PSMA-PET-CT(PSMA-PET-CT)阳性疾病,东部肿瘤协作组的表现状态为0-2,至少有两个恩杂鲁胺早期进展的危险因素。参与者是由中央集权随机分配的(1:1),基于网络的系统,使用带有随机分量的最小化来对研究地点进行分层,疾病负担,早期使用多西他赛,和以前用醋酸阿比特龙治疗。患者每天单独口服恩杂鲁胺160mg,或每6-8周静脉注射7·5GBq[177Lu]Lu-PSMA-617,这取决于临时PSMA-PET-CT(第12周)。主要终点是前列腺特异性抗原(PSA)无进展生存期,定义为从随机化日期到PSA进展的首次证据日期的间隔,开始非协议抗癌治疗,或死亡。分析是在意向治疗人群中进行的,使用分层Cox比例风险回归。该试验已在ClinicalTrials.gov注册,NCT04419402,参与者随访正在进行中。
结果:162名参与者在2020年8月17日至2022年7月26日之间被随机分配。83名男性被分配到恩扎鲁他胺加[177Lu]Lu-PSMA-617组,79人被分配到恩扎鲁他胺组.本中期分析的中位随访时间为20个月(IQR18-21),在数据截止日期,恩杂鲁胺+[177Lu]Lu-PSMA-617组83例患者中的32例(39%)和恩杂鲁胺组79例患者中的16例(20%)仍在接受治疗。中位年龄为71岁(IQR64-76)。恩杂鲁胺联合[177Lu]Lu-PSMA-617组的PSA无进展生存期中位数为13·0个月(95%CI11·0-17·0),恩杂鲁胺组为7·8个月(95%CI4·3-11·0)(风险比0·43,95%CI0·29-0·63,p<0·0001)。最常见的不良事件(所有等级)是疲劳(81例患者中有61例[75%])。恶心(38[47%]),恩杂鲁胺加[177Lu]Lu-PSMA-617组的口干(32[40%])和疲劳(79中的55[70%]),恶心(21[27%]),和便秘(18[23%])在恩杂鲁胺组。恩杂鲁胺加[177Lu]Lu-PSMA-617组81例患者中有32例(40%)发生3-5级不良事件,恩杂鲁胺组79例患者中有32例(41%)发生。仅在恩杂鲁胺加[177Lu]Lu-PSMA-617组中发生的3级事件包括贫血(81名参与者中的3名[4%])和血小板计数降低(1名[1%]名参与者)。在任何一组中,中央检查均未将4级或5级事件归因于治疗。
结论:恩杂鲁胺中添加[177Lu]Lu-PSMA-617可改善PSA无进展生存期,这提供了具有早期进展危险因素的转移性去势抵抗性前列腺癌患者抗癌活性增强的证据,并保证在转移性前列腺癌中更广泛地评估该组合。
背景:前列腺癌研究联盟(Movember和澳大利亚联邦政府),圣文森特诊所基金会,GenesisCare,罗伊·摩根研究,和Endocyte(诺华公司)。
BACKGROUND: Enzalutamide and lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this
study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [177Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer.
METHODS: ENZA-p was an open-label, randomised, controlled phase 2
trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for
study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This
trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing.
RESULTS: 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [177Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [177Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group.
CONCLUSIONS: The addition of [177Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer.
BACKGROUND: Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent\'s Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).