英国伦敦大学学院Gerhardt Attard团队研究了醋酸阿比特龙和泼尼松龙联合或不联合恩杂鲁胺治疗高危非转移性前列腺癌的疗效和安全性。该项研究成果发表在2021年12月23日出版的《柳叶刀》杂志上。

高危非转移性前列腺癌男性需采用雄激素剥夺疗法（ADT）治疗3年，通常联合放疗。研究组分析了两项随机对照3期临床试验的新数据，该试验在多组、多阶段平台协议中进行，以评估ADT患者人群中单独添加阿比特龙和泼尼松龙或恩杂鲁胺的疗效。

这些开放标签的3期临床试验在英国和瑞士的113个机构进行。符合条件的患者（无年龄限制）具有高危（定义为淋巴结阳性，如果淋巴结阴性，则至少有以下两种情况：肿瘤分期T3或T4期、Gleason评分为8-10分、前列腺特异性抗原[PSA]浓度≥40 ng/mL）或复发高风险特征（总ADT≤12个月、间隔≥12个月未治疗、PSA浓度≥4 ng/mL、倍增时间<6个月，或PSA浓度≥20 ng/mL，或结节性复发）的非转移性前列腺癌，WHO表现状态为0-2。

对淋巴结阴性的患者强制进行局部放疗（根据当地指南，对前列腺和精囊进行37Gy的局部放射治疗，或使用低分割计划进行等效放射治疗），而对淋巴结阳性的患者则鼓励进行局部放疗。在两个试验中，患者被按1：1随机分配，分为可包括手术和黄体生成素释放激素激动剂和拮抗剂的单独ADT（对照组），或ADT联合口服醋酸阿比特龙和泼尼松龙（联合治疗组）。在没有重复对照的第二项试验中，联合治疗组也接受恩杂鲁胺口服治疗。

给予ADT治疗3年，联合治疗2年，如果可以继续治疗而不进行局部放疗则除外。在初步分析中，研究组使用荟萃分析方法来汇集两个试验的事件。主要终点是无转移生存期。次要终点为总生存期、前列腺癌特异性生存期、无生化失败生存期、无进展生存期、毒性和不良事件。根据随机分配的治疗开始，在意向治疗人群中评估疗效和安全性。

2011年11月15日至2016年3月31日，1974名患者被随机分配接受治疗。第一个试验中对照组455名，联合治疗组459名；第二个试验包括恩杂鲁胺，对照组533名，联合治疗组527名。所有组的中位年龄为68岁，中位PSA为34 ng/ml；1974例患者中有774例（39%）淋巴结阳性，1684例（85%）计划接受放疗。

中位随访72个月后，联合治疗组有180例患者无转移生存，对照组有306例。联合治疗组的无转移生存期显著长于对照组。联合治疗组6年无转移生存率为82%，对照组为69%。当恩杂鲁胺和醋酸阿比特龙同时使用时，与单独使用醋酸阿比特龙相比，没有证据表明无转移生存期存在差异，且没有证据表明试验间存在异质性。

联合治疗组的总生存期、前列腺癌特异性生存期、无生化失败生存期和无进展生存期均显著长于对照组。在阿比特龙试验中，联合治疗组451例患者中有169例（37%）报告了3级及以上的不良事件，对照组455例患者中有130例（29%）。在阿比特龙和恩杂鲁胺试验中，联合治疗组513例患者中298例（58%）报告了3级及以上的不良事件，对照组533例患者中172例（32%）。

联合治疗组最常见的两个不良事件分别是高血压和丙氨酸转氨酶升高。共发生7例5级不良事件：对照组没有，醋酸阿比特龙和泼尼松龙组有3例（直肠腺癌、肺出血和呼吸系统疾病各1例），醋酸阿比特龙和泼尼松龙加恩杂鲁胺组有4例（2例败血性休克，2例猝死）。

研究结果表明，对于高危非转移性前列腺癌男性患者，联合治疗与单药ADT相比具有更高的无转移生存率。醋酸阿比特龙和泼尼松龙可作为该人群的新标准治疗。

附：英文原文

Title: Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol

Author: Gerhardt Attard, Laura Murphy, Noel W Clarke, William Cross, Robert J Jones, Christopher C Parker, Silke Gillessen, Adrian Cook, Chris Brawley, Claire L Amos, Nafisah Atako, Cheryl Pugh, Michelle Buckner, Simon Chowdhury, Zafar Malik, J Martin Russell, Clare Gilson, Hannah Rush, Jo Bowen, Anna Lydon, Ian Pedley, Joe M OSullivan, Alison Birtle, Joanna Gale, Narayanan Srihari, Carys Thomas, Jacob Tanguay, John Wagstaff, Prantik Das, Emma Gray, Mymoona Alzoueb, Omi Parikh, Angus Robinson, Isabel Syndikus, James Wylie, Anjali Zarkar, George Thalmann, Johann S de Bono, David P Dearnaley, Malcolm D Mason, Duncan Gilbert, Ruth E Langley, Robin Millman, David Matheson, Matthew R Sydes, Louise C Brown, Mahesh K B Parmar, Nicholas D James, Elin Jones, Katherine Hyde, Hilary Glen, Sarah Needleman, Ursula McGovern, Denise Sheehan, Sangeeta Paisey, Richard Shaffer, Mark Beresford, Zafar Malik, Anjali Zarkar, Emilio Porfiri, David Fackrell, Ling Lee, Thiagarajan Sreenivasan, Sue Brock, Simon Brown, Amit Bahl, Mike Smith-Howell, Cathryn Woodward, Mau-Don Phan, Danish Mazhar, Krishna Narahari, Jacob Tanguay, Fiona Douglas, Anil Kumar, Abdel Hamid, Azman Ibrahim, Dakshinamoorthy Muthukumar, Matthew Simms, Jane Worlding, Anna Tran, Mohammed Kagzi, Prantik Das, Carmel Pezaro, Virgil Sivoglo, Benjamin Masters, Pek Keng-Koh, Caroline Manetta, Duncan McLaren, Nishi Gupta, Denise Sheehan, Stergios Boussios, Henry Taylor, John Graham, Carla Perna, Lucinda Melcher, Warren Grant, Katherine Hyde, Ami Sabharwal

Issue&Volume: 2021-12-23

Abstract:

Background

Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population.

Methods

These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8–10, and prostate-specific antigen [PSA] concentration ≥40 ng/mL) or relapsing with high-risk features (≤12 months of total ADT with an interval of ≥12 months without treatment and PSA concentration ≥4 ng/mL with a doubling time of <6 months, or a PSA concentration ≥20 ng/mL, or nodal relapse) non-metastatic prostate cancer, and a WHO performance status of 0–2. Local radiotherapy (as per local guidelines, 74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules) was mandated for node negative and encouraged for node positive disease. In both trials, patients were randomly assigned (1:1), by use of a computerised algorithm, to ADT alone (control group), which could include surgery and luteinising-hormone-releasing hormone agonists and antagonists, or with oral abiraterone acetate (1000 mg daily) and oral prednisolone (5 mg daily; combination-therapy group). In the second trial with no overlapping controls, the combination-therapy group also received enzalutamide (160 mg daily orally). ADT was given for 3 years and combination therapy for 2 years, except if local radiotherapy was omitted when treatment could be delivered until progression. In this primary analysis, we used meta-analysis methods to pool events from both trials. The primary endpoint of this meta-analysis was metastasis-free survival. Secondary endpoints were overall survival, prostate cancer-specific survival, biochemical failure-free survival, progression-free survival, and toxicity and adverse events. For 90% power and a one-sided type 1 error rate set to 1·25% to detect a target hazard ratio for improvement in metastasis-free survival of 0·75, approximately 315 metastasis-free survival events in the control groups was required. Efficacy was assessed in the intention-to-treat population and safety according to the treatment started within randomised allocation. STAMPEDE is registered with ClinicalTrials.gov, NCT00268476, and with the ISRCTN registry, ISRCTN78818544.

Findings

Between Nov 15, 2011, and March 31, 2016, 1974 patients were randomly assigned to treatment. The first trial allocated 455 to the control group and 459 to combination therapy, and the second trial, which included enzalutamide, allocated 533 to the control group and 527 to combination therapy. Median age across all groups was 68 years (IQR 63–73) and median PSA 34 ng/ml (14·7–47); 774 (39%) of 1974 patients were node positive, and 1684 (85%) were planned to receive radiotherapy. With median follow-up of 72 months (60–84), there were 180 metastasis-free survival events in the combination-therapy groups and 306 in the control groups. Metastasis-free survival was significantly longer in the combination-therapy groups (median not reached, IQR not evaluable [NE]–NE) than in the control groups (not reached, 97–NE; hazard ratio [HR] 0·53, 95% CI 0·44–0·64, p<0·0001). 6-year metastasis-free survival was 82% (95% CI 79–85) in the combination-therapy group and 69% (66–72) in the control group. There was no evidence of a difference in metatasis-free survival when enzalutamide and abiraterone acetate were administered concurrently compared with abiraterone acetate alone (interaction HR 1·02, 0·70–1·50, p=0·91) and no evidence of between-trial heterogeneity (I2 p=0·90). Overall survival (median not reached [IQR NE–NE] in the combination-therapy groups vs not reached [103–NE] in the control groups; HR 0·60, 95% CI 0·48–0·73, p<0·0001), prostate cancer-specific survival (not reached [NE–NE] vs not reached [NE–NE]; 0·49, 0·37–0·65, p<0·0001), biochemical failure-free-survival (not reached [NE–NE] vs 86 months [83–NE]; 0·39, 0·33–0·47, p<0·0001), and progression-free-survival (not reached [NE–NE] vs not reached [103–NE]; 0·44, 0·36–0·54, p<0·0001) were also significantly longer in the combination-therapy groups than in the control groups. Adverse events grade 3 or higher during the first 24 months were, respectively, reported in 169 (37%) of 451 patients and 130 (29%) of 455 patients in the combination-therapy and control groups of the abiraterone trial, respectively, and 298 (58%) of 513 patients and 172 (32%) of 533 patients of the combination-therapy and control groups of the abiraterone and enzalutamide trial, respectively. The two most common events more frequent in the combination-therapy groups were hypertension (abiraterone trial: 23 (5%) in the combination-therapy group and six (1%) in control group; abiraterone and enzalutamide trial: 73 (14%) and eight (2%), respectively) and alanine transaminitis (abiraterone trial: 25 (6%) in the combination-therapy group and one (<1%) in control group; abiraterone and enzalutamide trial: 69 (13%) and four (1%), respectively). Seven grade 5 adverse events were reported: none in the control groups, three in the abiraterone acetate and prednisolone group (one event each of rectal adenocarcinoma, pulmonary haemorrhage, and a respiratory disorder), and four in the abiraterone acetate and prednisolone with enzalutamide group (two events each of septic shock and sudden death).

Interpretation

Among men with high-risk non-metastatic prostate cancer, combination therapy is associated with significantly higher rates of metastasis-free survival compared with ADT alone. Abiraterone acetate with prednisolone should be considered a new standard treatment for this population.

DOI: 10.1016/S0140-6736(21)02437-5

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02437-5/fulltext