NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia.
Department of Radiation Oncology, National University Cancer Institute, Singapore, Singapore.
JAMA Netw Open. 2024 Sep 3;7(9):e2433863. doi: 10.1001/jamanetworkopen.2024.33863.
IMPORTANCE: Observed treatment effects on overall survival (OS) differed substantially in the first 2 randomized clinical trials of lutetium Lu 177 vipivotide tetraxetan (Lu-177) prostate-specific membrane antigen (PSMA) in metastatic castration-resistant prostate cancer. OBJECTIVE: To investigate factors associated with the observed difference in treatment effects on OS, including differences in the risk of crossover from randomized treatment after disease progression. DESIGN, SETTING, AND PARTICIPANTS: This comparative effectiveness study used individual participant data from 2 randomized clinical trials, TheraP (A Randomised Phase 2 Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer [ANZUP Protocol 1603]) (n = 200), recruited from February 2018 to September 2019 in Australia, and published data from VISION (An International, Prospective, Open Label, Multicenter, Randomized Phase 3 Study of 177Lu-PSMA-617 in the Treatment of Patients With Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer) (n = 831), recruited from June 2018 to October 2019 in North America and Europe. Individual participant data for OS were reconstructed from VISION using the published survival curves. Data were analyzed February 6, 2018, to December 31, 2021, for TheraP and June 4, 2018, to January 27, 2021, for VISION. INTERVENTIONS: TheraP randomized participants to receive treatment with Lu-177 PSMA or cabazitaxel. VISION randomized participants to receive treatment with or without Lu-177 PSMA in addition to physicians' choice of protocol-permitted treatments (PPT; approved hormonal treatments [such as abiraterone and enzalutamide], bisphosphonates, radiotherapy, denosumab, or glucocorticoids), excluding cabazitaxel. MAIN OUTCOMES AND MEASURES: Patient characteristics, treatment protocols, and OS outcomes of the 2 trials were compared. Estimates of the effect on OS from TheraP were adjusted for crossover from randomly assigned treatment using a rank-preserving structural failure time model (RPSFTM) and inverse probability of censoring weights (IPCW) methods. RESULTS: The 200 participants in TheraP and 831 participants in VISION were similar in age (median [range], 72 [49-86] vs 71 [40-94] years). Improved OS was observed in the comparator treatment group (cabazitaxel) in TheraP compared with VISION (PPT) (hazard ratio [HR], 0.53 [95% CI, 0.39-0.71]). The Lu-177 PSMA treatment groups in TheraP and VISION had similar OS (HR, 0.92 [95% CI, 0.70-1.19]). In TheraP, 20 of 101 participants in the cabazitaxel group crossed over to Lu-177 PSMA, while 32 of 99 participants in the Lu-177 PSMA arm crossed over to cabazitaxel. No statistically significant differences in OS between the Lu-177 PSMA and cabazitaxel groups of TheraP were observed after controlling for crossover to cabazitaxel: RPSFTM HR, 0.97 (95% CI, 0.60-1.58); IPCW HR, 0.92 (95% CI, 0.65-1.32); RPSFTM HR, 0.97 (95% CI, 0.60-1.58) and IPCW HR, 0.82 (95% CI, 0.54-1.24) for crossover to Lu-177 PSMA; RPSFTM HR, 0.96 (95% CI, 0.53-1.74) and IPCW HR, 0.82 (95% CI, 0.53-1.27) for crossover to either Lu-177 PSMA or cabazitaxel. CONCLUSIONS AND RELEVANCE: Findings of this secondary analysis of the TheraP and VISION randomized clinical trials suggest that the choice of comparator treatments (ie, cabazitaxel vs PPT) may explain the difference in the observed effect of Lu-177 PSMA on OS between the 2 trials. Causal inference methods such as RPSFTM and IPCW may help rule out crossover as a plausible explanation.
重要性：在前 2 项随机临床试验中，观察到的总体生存（OS）治疗效果在转移性去势抵抗性前列腺癌的镥 Lu177 放射性核素 vipivotide 四氮烯（Lu-177）前列腺特异性膜抗原（PSMA）中存在显著差异。
目的：研究与 OS 观察到的治疗效果差异相关的因素，包括疾病进展后随机治疗交叉的差异。
设计、设置和参与者：这项比较有效性研究使用了来自澳大利亚的两项随机临床试验的个体参与者数据，TheraP（一项 177Lu-PSMA617 治疗与卡巴他赛在转移性去势抵抗性前列腺癌中的随机 2 期试验 [ANZUP 方案 1603]）（n=200），招募时间为 2018 年 2 月至 2019 年 9 月，以及来自北美和欧洲的 VISION（一项国际、前瞻性、开放标签、多中心、随机 3 期研究，评估 177Lu-PSMA-617 治疗进展性 PSMA 阳性转移性去势抵抗性前列腺癌患者的疗效）（n=831）的已发表数据，招募时间为 2018 年 6 月至 2019 年 10 月。使用发表的生存曲线，从 VISION 中重建 OS 的个体参与者数据。数据分析时间为 2018 年 2 月 6 日至 2021 年 12 月 31 日（TheraP）和 2018 年 6 月 4 日至 2021 年 1 月 27 日（VISION）。
干预措施：TheraP 将参与者随机分配接受 Lu-177 PSMA 或卡巴他赛治疗。VISION 将参与者随机分配接受 Lu-177 PSMA 加或不加医生选择的协议允许的治疗（批准的激素治疗[如阿比特龙和恩扎鲁胺]、双膦酸盐、放疗、地诺单抗或糖皮质激素），不包括卡巴他赛。
主要结果和措施：比较了两项试验的患者特征、治疗方案和 OS 结局。使用等级保持结构失效时间模型（RPSFTM）和逆概率删失权重（IPCW）方法调整了 TheraP 对 OS 的估计，以校正从随机分配的治疗交叉。
结果：TheraP 的 200 名参与者和 VISION 的 831 名参与者在年龄方面相似（中位数[范围]，72[49-86]岁 vs 71[40-94]岁）。与 VISION（PPT）相比，TheraP 中比较治疗组（卡巴他赛）的 OS 得到改善（危险比[HR]，0.53[95%CI，0.39-0.71]）。TheraP 和 VISION 中 Lu-177 PSMA 治疗组的 OS 相似（HR，0.92[95%CI，0.70-1.19]）。TheraP 中，101 名卡巴他赛组的 20 名参与者交叉至 Lu-177 PSMA 组，而 99 名 Lu-177 PSMA 组的 32 名参与者交叉至卡巴他赛组。TheraP 中 Lu-177 PSMA 和卡巴他赛组之间的 OS 差异在控制交叉至卡巴他赛后没有统计学意义：RPSFTM HR，0.97（95%CI，0.60-1.58）；IPCW HR，0.92（95%CI，0.65-1.32）；RPSFTM HR，0.97（95%CI，0.60-1.58）和 IPCW HR，0.82（95%CI，0.54-1.24）交叉至 Lu-177 PSMA；RPSFTM HR，0.96（95%CI，0.53-1.74）和 IPCW HR，0.82（95%CI，0.53-1.27）交叉至 Lu-177 PSMA 或卡巴他赛。
结论和相关性：这项 TheraP 和 VISION 随机临床试验的二次分析结果表明，选择比较治疗（即卡巴他赛与 PPT）可能解释了两项试验中 Lu-177 PSMA 对 OS 观察到的治疗效果差异。RPSFTM 和 IPCW 等因果推理方法可能有助于排除交叉作为合理的解释。
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