法国巴黎萨克雷大学Karim Fizazi团队研究了阿比特龙加强的松联合雄激素剥夺疗法和多西紫杉醇治疗新发转移性去势敏感性前列腺癌的疗效和安全性。该研究于2022年4月8日发表在《柳叶刀》杂志上。

转移性去势敏感性前列腺癌的现行治疗标准补充了多西紫杉醇、第二代激素疗法或放疗的雄激素剥夺疗法。该研究旨在评估阿比特龙加泼尼松（加或不加放疗）联合标准治疗的疗效和安全性。

研究组在比利时、法国、爱尔兰、意大利、罗马尼亚、西班牙和瑞士的77家医院进行了一项开放标签、随机、3期临床、2*2析因设计研究，招募男性、年龄在18岁或以上、经组织学或细胞学证实为新发转移性前列腺癌、东部肿瘤合作组的表现状态为0-1（或因骨痛状态为2）的患者。

将参与者按1:1:1:1随机分组，分别为标准治疗组（单用雄激素剥夺疗法或每3周静脉注射多西紫杉醇75mg/m²一次）、标准治疗组加放疗组、标准治疗加阿比特龙组（每天一次口服1000mg阿比特龙加每天两次口服5mg强的松）或标准治疗加放疗加阿比特龙组。

无论是研究人员还是患者都不知晓治疗分配。主要终点是无进展生存率和总生存率。首先在总体人群中评估阿比特龙的疗效，然后在以多西紫杉醇为标准治疗、接受雄激素剥夺治疗的人群中评估疗效（意向人群）。

2013年11月27日至2018年12月20日，研究组共登记了1173名患者（其中1名患者随后撤回了对其数据进行分析的同意书），将其随机分配接受标准护理（296名）、标准护理加放疗（293名）、标准护理加阿比特龙（292名）或标准护理加放疗加阿比特龙（291名）。

影像学无进展生存期的中位随访时间为3.5年，总生存期的中位随访时间为4.4年。校正后的Cox回归模型显示，阿比特龙与放疗之间没有相互作用，因此可以对阿比特龙的疗效进行汇总分析。

在总体人群中，与未接受阿比特龙治疗的患者（589名）相比，接受阿比特龙治疗的患者（583名）其影像学无进展生存期（危险比为0.54）和总生存期（0.82）更长。在使用多西紫杉醇的雄激素剥夺治疗人群中，与未接受阿比特龙治疗的患者（355名）相比，接受阿比特龙治疗的患者（355名）其影像学无进展生存期（0.50）和总生存期（0.75）亦更长。

在使用多西紫杉醇的雄激素剥夺治疗人群中，347名接受阿比特龙治疗的患者中有217名（63%）发生3级或更严重的不良事件，350名未接受阿比特龙治疗的患者中有181名（52%）；高血压的发生率差异最大（分别为76例[22%]和45例[13%]）。

与雄激素剥夺治疗加多西紫杉醇相比，在雄激素剥夺治疗加多西紫杉醇中添加阿比特龙不会增加中性粒细胞减少、发热性中性粒细胞减少、疲劳或神经病变的发生率。

研究结果表明，联合雄激素剥夺疗法、多西紫杉醇和阿比特龙治疗新发转移性去势敏感性前列腺癌可提高总生存率和无进展生存率，毒性（主要是高血压）适度增加。这种三联疗法可以成为这些患者的标准治疗。

附：英文原文

Title: Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2×2 factorial design

Author: Karim Fizazi, Stéphanie Foulon, Joan Carles, Guilhem Roubaud, Ray McDermott, Aude Fléchon, Bertrand Tombal, Stéphane Supiot, Dominik Berthold, Philippe Ronchin, Gabriel Kacso, Gwenalle Gravis, Fabio Calabro, Jean-Franois Berdah, Ali Hasbini, Marlon Silva, Antoine Thiery-Vuillemin, Igor Latorzeff, Loc Mourey, Brigitte Laguerre, Sophie Abadie-Lacourtoisie, Etienne Martin, Claude El Kouri, Anne Escande, Alvar Rosello, Nicolas Magne, Friederike Schlurmann, Frank Priou, Marie-Eve Chand-Fouche, Salvador Villà Freixa, Muhammad Jamaluddin, Isabelle Rieger, Alberto Bossi

Issue&Volume: 2022-04-08

Abstract:

Background

Current standard of care for metastatic castration-sensitive prostate cancer supplements androgen deprivation therapy with either docetaxel, second-generation hormonal therapy, or radiotherapy. We aimed to evaluate the efficacy and safety of abiraterone plus prednisone, with or without radiotherapy, in addition to standard of care.

Methods

We conducted an open-label, randomised, phase 3 study with a 2×2 factorial design (PEACE-1) at 77 hospitals across Belgium, France, Ireland, Italy, Romania, Spain, and Switzerland. Eligible patients were male, aged 18 years or older, with histologically confirmed or cytologically confirmed de novo metastatic prostate adenocarcinoma, and an Eastern Cooperative Oncology Group performance status of 0–1 (or 2 due to bone pain). Participants were randomly assigned (1:1:1:1) to standard of care (androgen deprivation therapy alone or with intravenous docetaxel 75 mg/m2 once every 3 weeks), standard of care plus radiotherapy, standard of care plus abiraterone (oral 1000 mg abiraterone once daily plus oral 5 mg prednisone twice daily), or standard of care plus radiotherapy plus abiraterone. Neither the investigators nor the patients were masked to treatment allocation. The coprimary endpoints were radiographic progression-free survival and overall survival. Abiraterone efficacy was first assessed in the overall population and then in the population who received androgen deprivation therapy with docetaxel as standard of care (population of interest). This study is ongoing and is registered with ClinicalTrials.gov, NCT01957436.

Findings

Between Nov 27, 2013, and Dec 20, 2018, 1173 patients were enrolled (one patient subsequently withdrew consent for analysis of his data) and assigned to receive standard of care (n=296), standard of care plus radiotherapy (n=293), standard of care plus abiraterone (n=292), or standard of care plus radiotherapy plus abiraterone (n=291). Median follow-up was 3·5 years (IQR 2·8–4·6) for radiographic progression-free survival and 4·4 years (3·5–5·4) for overall survival. Adjusted Cox regression modelling revealed no interaction between abiraterone and radiotherapy, enabling the pooled analysis of abiraterone efficacy. In the overall population, patients assigned to receive abiraterone (n=583) had longer radiographic progression-free survival (hazard ratio [HR] 0·54, 99·9% CI 0·41–0·71; p<0·0001) and overall survival (0·82, 95·1% CI 0·69–0·98; p=0·030) than patients who did not receive abiraterone (n=589). In the androgen deprivation therapy with docetaxel population (n=355 in both with abiraterone and without abiraterone groups), the HRs were consistent (radiographic progression-free survival 0·50, 99·9% CI 0·34–0·71; p<0·0001; overall survival 0·75, 95·1% CI 0·59–0·95; p=0·017). In the androgen deprivation therapy with docetaxel population, grade 3 or worse adverse events occurred in 217 (63%) of 347 patients who received abiraterone and 181 (52%) of 350 who did not; hypertension had the largest difference in occurrence (76 [22%] patients and 45 [13%], respectively). Addition of abiraterone to androgen deprivation therapy plus docetaxel did not increase the rates of neutropenia, febrile neutropenia, fatigue, or neuropathy compared with androgen deprivation therapy plus docetaxel alone.

Interpretation

Combining androgen deprivation therapy, docetaxel, and abiraterone in de novo metastatic castration-sensitive prostate cancer improved overall survival and radiographic progression-free survival with a modest increase in toxicity, mostly hypertension. This triplet therapy could become a standard of care for these patients.

DOI: 10.1016/S0140-6736(22)00367-1

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00367-1/fulltext