英国伦敦癌症研究所Johann S de Bono团队研究了Ipatasertib联合阿比特龙和泼尼松龙治疗转移性去势抵抗前列腺癌的疗效。2021年7月10日出版的《柳叶刀》杂志发表了这项成果。

PI3K/AKT和雄激素受体通路在转移性去势抵抗性前列腺癌（mCRPCs）中失调；功能性PTEN缺失状态的肿瘤具有过度激活的AKT信号。AKT抑制剂ipatasertib联合阿比特龙的双途径抑制可能比单用阿比特龙有更大的益处。该研究旨在比较ipatasertib联合阿比特龙与安慰剂联合阿比特龙治疗先前未经治疗的mCRPC伴或不伴肿瘤PTEN缺失患者的疗效。

研究组在26个国家或地区的200个机构进行了一项随机、双盲、临床3期试验，招募年龄在18岁或以上，既往未经治疗的无症状或轻度症状的mCRPC病情进展患者，东部肿瘤协作组的表现状态为0或1，将其按1：1随机分组，分别接受ipatasertib+阿比特龙+泼尼松龙治疗，或安慰剂+阿比特龙+泼尼松龙治疗。患者接受研究治疗，直到疾病进展、不能耐受的毒性、退出研究或研究完成。主要终点是研究者通过免疫组织化学方法评估PTEN缺失人群和意向治疗人群的影像学无进展生存率。

2017年6月30日至2019年1月17日，共有1101名患者入组，其中安慰剂-阿比特龙组554名，ipatasertib-阿比特龙组547名。中位随访时间为19个月。在521例经免疫组化确定PTEN缺失的肿瘤患者中，安慰剂-阿比特龙组261位患者的中位无进展生存期为16.5个月，显著短于ipatasertib-阿比特龙组260位患者的18.5个月。在意向治疗人群中，安慰剂-阿比特龙组的中位无进展生存期为16.6个月，短于ipatasertib-阿比特龙组的19.2个月。

安慰剂-阿比特龙组546例患者中有213例（39%）发生3级或更高级别的不良事件，ipatasertib-阿比特龙组551例患者中有386例（70%）；安慰剂-阿比特龙组中有28例（5%）发生了导致停药的不良事件，ipatasertib-阿比特龙组中有116例（21%）停药。安慰剂-阿比特龙组中有2例患者因治疗相关的不良事件死亡，其中1例急性心肌梗死，1例下呼吸道感染；Ipatasertib-阿比特龙组也有2例患者死亡，其中1例高血糖，1例化学性肺炎。

研究结果表明，与安慰剂加阿比特龙相比，ipatasertib联合阿比特龙可显著改善PTEN缺失肿瘤患者的影像学无进展生存率。不良事件与每种药物的已知安全性一致。

附：英文原文

Title: Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial

Author: Christopher Sweeney, Sergio Bracarda, Cora N Sternberg, Kim N Chi, David Olmos, Shahneen Sandhu, Christophe Massard, Nobuaki Matsubara, Boris Alekseev, Francis Parnis, Vagif Atduev, Gary L Buchschacher, Rustem Gafanov, Luis Corrales, Michael Borre, Daniil Stroyakovskiy, Gustavo Vasconcelos Alves, Evangelos Bournakis, Javier Puente, Marie-Laurence Harle-Yge, Jorge Gallo, Geng Chen, Justin Hanover, Matthew J Wongchenko, Josep Garcia, Johann S de Bono

Issue&Volume: 2021/07/10

Abstract:

Background

The PI3K/AKT and androgen-receptor pathways are dysregulated in metastatic castration-resistant prostate cancers (mCRPCs); tumours with functional PTEN-loss status have hyperactivated AKT signalling. Dual pathway inhibition with AKT inhibitor ipatasertib plus abiraterone might have greater benefit than abiraterone alone. We aimed to compare ipatasertib plus abiraterone with placebo plus abiraterone in patients with previously untreated mCRPC with or without tumour PTEN loss.

Methods

We did a randomised, double-blind, phase 3 trial at 200 sites across 26 countries or regions. Patients aged 18 years or older with previously untreated asymptomatic or mildly symptomatic mCRPC who had progressive disease and Eastern Collaborative Oncology Group performance status of 0 or 1 were randomly assigned (1:1; permuted block method) to receive ipatasertib (400 mg once daily orally) plus abiraterone (1000 mg once daily orally) and prednisolone (5 mg twice a day orally) or placebo plus abiraterone and prednisolone (with the same dosing schedule). Patients received study treatment until disease progression, intolerable toxicity, withdrawal from the study, or study completion. Stratification factors were previous taxane-based therapy for hormone-sensitive prostate cancer, type of progression, presence of visceral metastasis, and tumour PTEN-loss status by immunohistochemistry. Patients, investigators, and the study sponsor were masked to the treatment allocation. The coprimary endpoints were investigator-assessed radiographical progression-free survival in the PTEN-loss-by-immunohistochemistry population and in the intention-to-treat population. This study is ongoing and is registered with ClinicalTrials.gov, NCT03072238.

Findings

Between June 30, 2017, and Jan 17, 2019, 1611 patients were screened for eligibility and 1101 (68%) were enrolled; 554 (50%) were assigned to the placebo–abiraterone group and 547 (50%) to the ipatasertib–abiraterone group. At data cutoff (March 16, 2020), median follow-up duration was 19 months (range 0–33). In the 521 (47%) patients who had tumours with PTEN loss by immunohistochemistry (261 in the placebo–abiraterone group and 260 in the ipatasertib–abiraterone group), median radiographical progression-free survival was 16·5 months (95% CI 13·9–17·0) in the placebo–abiraterone group and 18·5 months (16·3–22·1) in the ipatasertib–abiraterone group (hazard ratio [HR] 0·77 [95% CI 0·61–0·98]; p=0·034; significant at α=0·04). In the intention-to-treat population, median progression-free survival was 16·6 months (95% CI 15·6–19·1) in the placebo–abiraterone group and 19·2 months (16·5–22·3) in the ipatasertib–abiraterone group (HR 0·84 [95% CI 0·71–0·99]; p=0·043; not significant at α=0·01). Grade 3 or higher adverse events occurred in 213 (39%) of 546 patients in the placebo–abiraterone group and in 386 (70%) of 551 patients in the ipatasertib–abiraterone group; adverse events leading to discontinuation of placebo or ipatasertib occurred in 28 (5%) in the placebo–abiraterone group and 116 (21%) in the ipatasertib–abiraterone group. Deaths due to adverse events deemed related to treatment occurred in two patients (<1%; acute myocardial infarction [n=1] and lower respiratory tract infection [n=1]) in the placebo–abiraterone group and in two patients (<1%; hyperglycaemia [n=1] and chemical pneumonitis [n=1]) in the ipastasertb–abiraterone group.

Interpretation

Ipatasertib plus abiraterone significantly improved radiographical progression-free survival compared with placebo plus abiraterone among patients with mCRPC with PTEN-loss tumours, but there was no significant difference between the groups in the intention-to-treat population. Adverse events were consistent with the known safety profiles of each agent. These data suggest that combined AKT and androgen-receptor signalling pathway inhibition with ipatasertib and abiraterone is a potential treatment for men with PTEN-loss mCRPC, a population with a poor prognosis.

DOI: 10.1016/S0140-6736(21)00580-8

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00580-8/fulltext