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.
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.
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醋酸阿比特龙和泼尼松龙联合或不联合enzalutamide治疗高危非转移性前列腺癌：STAMPEDE平台方案两项随机对照III期试验主要结果的荟萃分析
DOI：
10.1016/s0140-6736(21)02437-5
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发表时间：
2022-01-29
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Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators
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Attard G;Murphy L;Clarke NW;Cross W;Jones RJ;Parker CC;Gillessen S;Cook A;Brawley C;Amos CL;Atako N;Pugh C;Buckner M;Chowdhury S;Malik Z;Russell JM;Gilson C;Rush H;Bowen J;Lydon A;Pedley I;O'Sullivan JM;Birtle A;Gale J;Srihari N;Thomas C;Tanguay J;Wagstaff J;Das P;Gray E;Alzoueb M;Parikh O;Robinson A;Syndikus I;Wylie J;Zarkar A;Thalmann G;de Bono JS;Dearnaley DP;Mason MD;Gilbert D;Langley RE;Millman R;Matheson D;Sydes MR;Brown LC;Parmar MKB;James ND;Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators
高风险非转移性前列腺癌患者接受3年雄激素剥夺疗法（ADT），通常与放疗联合治疗。我们分析了来自两项随机对照3期试验的新数据，这些试验是在多组、多阶段平台方案中进行的，以评估在该患者群体中单独添加阿比特龙和泼尼松龙或与恩杂鲁胺进行ADT的疗效。这些开放标签的三期试验在英国和瑞士的113个地点进行。符合条件的患者（无年龄限制）为高风险患者(定义为淋巴结阳性，或者如果淋巴结阴性，至少具有以下两项：肿瘤分期T3或T4， Gleason sum评分为8-10分，前列腺特异性抗原[PSA]浓度≥40 ng/mL)或复发时具有高危特征（总ADT≤12个月，间隔≥12个月未治疗，PSA浓度≥4 ng/mL，翻倍时间<6个月，或PSA浓度≥20 ng/mL，或淋巴结复发）非转移性前列腺癌，WHO评分0-2分。局部放疗（根据当地指南，对前列腺和精囊进行37次74 Gy的局部放疗，或使用低分割时间表进行同等剂量的局部放疗）对于淋巴结阴性的疾病是强制性的，而对于淋巴结阳性的疾病则是鼓励的。在这两项试验中，患者被随机分配（1:1），通过使用计算机化算法，单独ADT（对照组），其中可能包括手术和黄体生成素释放激素激动剂和拮抗剂，或口服醋酸阿比特龙（每天1000毫克）和口服强的松龙（每天5毫克，联合治疗组）。在没有重叠对照的第二项试验中，联合治疗组也接受enzalutamide（每日口服160 mg）。ADT治疗3年，联合治疗2年，除非局部放疗可以给予治疗，直到进展。在本初步分析中，我们使用荟萃分析方法汇集了两个试验的事件。这项荟萃分析的主要终点是无转移生存期。次要终点是总生存期、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。对于90%的功效和设置为1.25%的单侧1型错误率，检测无转移生存改善的目标风险比为0.75，对照组中大约需要315个无转移生存事件。在意向治疗人群中评估疗效，并根据随机分配的治疗开始进行安全性评估。STAMPEDE在ClinicalTrials.gov注册，注册号为NCT00268476，在ISRCTN注册，注册号为ISRCTN78818544。在2011年11月15日至2016年3月31日期间，1974名患者被随机分配到治疗组。第一项试验分配给对照组455人，联合治疗459人，第二项试验，包括恩杂鲁胺，分配给对照组533人，联合治疗527人。各组的中位年龄为68岁（IQR为63-73），中位PSA为34 ng/ml (14.7 - 47)；1974例患者中淋巴结阳性774例（39%），计划放疗1684例（85%）。中位随访72个月（60-84），联合治疗组有180例无转移生存事件，对照组有306例。联合治疗组的无转移生存期（中位数未达到，IQR无法评估[NE] -NE）明显高于对照组（未达到，97-NE；风险比[HR] 0.53, 95% CI 0.44 - 0.64, p< 0.0001）。联合治疗组6年无转移生存率为82% (95% CI 79-85)，对照组为69%（66-72）。与单独给药阿比特龙相比，同时给药恩杂鲁胺和醋酸阿比特龙无转移生存期无差异（相互作用HR 1.02, 0.70 - 1.50, p= 0.91），无试验间异质性（I2 p= 0.90）。总生存期（联合治疗组中位未达到[IQR NE-NE] vs对照组未达到[103-NE]； HR 0.60, 95% CI 0.48 - 0.73, p< 0.0001），前列腺癌特异性生存期（未达到[NE-NE] vs未达到[NE-NE]； 0.49, 0.37 - 0.65, p< 0.0001），生化无衰竭生存期（未达到[NE-NE] vs 86个月[83-NE]； 0.39, 0.33 - 0.47, p< 0.0001），无进展生存期(未达到[NE-NE] vs未达到[103-NE]；（0.44, 0.36 - 0.54, p< 0.0001），联合治疗组的生存时间也明显长于对照组。阿比特龙联合治疗组和对照组451例患者中分别有169例（37%）和130例（29%）在前24个月报告了3级或以上不良事件，阿比特龙联合治疗组和对照组513例患者中分别有298例（58%）和533例患者中分别有172例（32%）发生不良事件。联合治疗组中最常见的两个事件是高血压(阿比特龙试验：联合治疗组23例（5%），对照组6例（1%）；阿比特龙联合恩杂鲁胺试验：73例（14%）和8例（2%）；丙氨酸转氨炎(阿比特龙联合治疗组：25例（6%），对照组1例（<1%）；阿比特龙和恩杂鲁胺试验：分别为69例（13%）和4例（1%）。报告了7例5级不良事件：对照组无一例，醋酸阿比特龙和泼尼松龙组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联合恩杂鲁胺组4例（感染性休克和猝死各2例）。在高风险非转移性前列腺癌患者中，联合治疗与单用ADT相比，无转移生存率显著提高。醋酸阿比特龙联合强的松龙应被视为这一人群的新标准治疗。英国癌症研究中心，英国医学研究委员会，瑞士临床癌症研究小组，杨森和安斯泰来。
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. 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. 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). 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. Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.