K Fizazi, K N Chi, N D Shore, K Herrmann, J S de Bono, D Castellano, J M Piulats, A Fléchon, X X Wei, H Mahammedi, G Roubaud, M Fleming, T Haas, S Ghebremariam, T N Kreisl, S Rajagopalan, O Sartor, M J Morris
{"title":"[177Lu]Lu-PSMA-617与紫杉烷初始转移性去势抵抗性前列腺癌患者雄激素受体途径抑制剂变化的3期PSMAfore试验的最终总生存期和安全性分析。","authors":"K Fizazi, K N Chi, N D Shore, K Herrmann, J S de Bono, D Castellano, J M Piulats, A Fléchon, X X Wei, H Mahammedi, G Roubaud, M Fleming, T Haas, S Ghebremariam, T N Kreisl, S Rajagopalan, O Sartor, M J Morris","doi":"10.1016/j.annonc.2025.07.003","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>In PSMAfore, [<sup>177</sup>Lu]Lu-PSMA-617 (<sup>177</sup>Lu-PSMA-617) prolonged radiographic progression-free survival (rPFS) in taxane-naive patients with metastatic castration-resistant prostate cancer (mCRPC), with a favourable safety profile, versus a change in androgen receptor pathway inhibitor (ARPI). We report the final overall survival (OS) analysis and updated safety data.</p><p><strong>Patients and methods: </strong>PSMAfore (NCT04689828) was an open-label, international, phase 3 trial. Patients with prostate-specific membrane antigen (PSMA)-positive mCRPC who had experienced disease progression once on a previous ARPI and were candidates for ARPI change were randomized 1:1 to <sup>177</sup>Lu-PSMA-617 or ARPI change to abiraterone or enzalutamide. Crossover from ARPI change to <sup>177</sup>Lu-PSMA-617 was allowed after centrally confirmed radiographic progression. Endpoints included rPFS (primary), OS (key secondary), and safety (secondary).</p><p><strong>Results: </strong>Patients were randomized to <sup>177</sup>Lu-PSMA-617 or ARPI change (n = 234 each): 141/234 participants (60.3%) randomized to ARPI change crossed over (75.4% of those with centrally confirmed radiographic progression). The median OS was 24.48 months (95% CI 19.55-28.94) with <sup>177</sup>Lu-PSMA-617 versus 23.13 (19.61-25.53) with ARPI change (hazard ratio [HR] 0.91 [95% CI 0.72-1.14]; p = 0.20) based on the intention-to-treat (ITT) principle; the crossover-adjusted OS HR by inverse probability of censoring weighting modelling was 0.59 (95% CI 0.38-0.91). For <sup>177</sup>Lu-PSMA-617 versus ARPI change, exposure-adjusted incidences of grade ≥ 3 and serious treatment-emergent adverse events were 60.8 versus 85.1 and 32.5 versus 49.9 per 100 patient-treatment years, respectively. Dry mouth occurred in 135/227 participants (59.5%; 2/227 grade ≥ 3) and anaemia in 62/227 (27.3%; 14/227 grade ≥ 3) in the <sup>177</sup>Lu-PSMA-617 arm.</p><p><strong>Conclusions: </strong>OS analyses did not show a statistically significant difference between the <sup>177</sup>Lu-PSMA-617 and ARPI arms based on the ITT principle; results were likely confounded by the high rate of crossover. The safety profile of <sup>177</sup>Lu-PSMA-617 was favourable with no new safety signals identified.</p>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":" ","pages":""},"PeriodicalIF":56.7000,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Final overall survival and safety analyses of the phase 3 PSMAfore trial of [<sup>177</sup>Lu]Lu-PSMA-617 versus change of androgen receptor pathway inhibitor in taxane-naive patients with metastatic castration-resistant prostate cancer.\",\"authors\":\"K Fizazi, K N Chi, N D Shore, K Herrmann, J S de Bono, D Castellano, J M Piulats, A Fléchon, X X Wei, H Mahammedi, G Roubaud, M Fleming, T Haas, S Ghebremariam, T N Kreisl, S Rajagopalan, O Sartor, M J Morris\",\"doi\":\"10.1016/j.annonc.2025.07.003\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>In PSMAfore, [<sup>177</sup>Lu]Lu-PSMA-617 (<sup>177</sup>Lu-PSMA-617) prolonged radiographic progression-free survival (rPFS) in taxane-naive patients with metastatic castration-resistant prostate cancer (mCRPC), with a favourable safety profile, versus a change in androgen receptor pathway inhibitor (ARPI). We report the final overall survival (OS) analysis and updated safety data.</p><p><strong>Patients and methods: </strong>PSMAfore (NCT04689828) was an open-label, international, phase 3 trial. Patients with prostate-specific membrane antigen (PSMA)-positive mCRPC who had experienced disease progression once on a previous ARPI and were candidates for ARPI change were randomized 1:1 to <sup>177</sup>Lu-PSMA-617 or ARPI change to abiraterone or enzalutamide. Crossover from ARPI change to <sup>177</sup>Lu-PSMA-617 was allowed after centrally confirmed radiographic progression. Endpoints included rPFS (primary), OS (key secondary), and safety (secondary).</p><p><strong>Results: </strong>Patients were randomized to <sup>177</sup>Lu-PSMA-617 or ARPI change (n = 234 each): 141/234 participants (60.3%) randomized to ARPI change crossed over (75.4% of those with centrally confirmed radiographic progression). The median OS was 24.48 months (95% CI 19.55-28.94) with <sup>177</sup>Lu-PSMA-617 versus 23.13 (19.61-25.53) with ARPI change (hazard ratio [HR] 0.91 [95% CI 0.72-1.14]; p = 0.20) based on the intention-to-treat (ITT) principle; the crossover-adjusted OS HR by inverse probability of censoring weighting modelling was 0.59 (95% CI 0.38-0.91). For <sup>177</sup>Lu-PSMA-617 versus ARPI change, exposure-adjusted incidences of grade ≥ 3 and serious treatment-emergent adverse events were 60.8 versus 85.1 and 32.5 versus 49.9 per 100 patient-treatment years, respectively. Dry mouth occurred in 135/227 participants (59.5%; 2/227 grade ≥ 3) and anaemia in 62/227 (27.3%; 14/227 grade ≥ 3) in the <sup>177</sup>Lu-PSMA-617 arm.</p><p><strong>Conclusions: </strong>OS analyses did not show a statistically significant difference between the <sup>177</sup>Lu-PSMA-617 and ARPI arms based on the ITT principle; results were likely confounded by the high rate of crossover. The safety profile of <sup>177</sup>Lu-PSMA-617 was favourable with no new safety signals identified.</p>\",\"PeriodicalId\":8000,\"journal\":{\"name\":\"Annals of Oncology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":56.7000,\"publicationDate\":\"2025-07-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.annonc.2025.07.003\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.annonc.2025.07.003","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景：在PSMAfore研究中，[177Lu]Lu-PSMA-617 （177Lu- psma -617）与雄激素受体途径抑制剂（ARPI）的变化相比，延长了紫杉醇初始化转移性去雄抵抗性前列腺癌（mCRPC）患者的放射无进展生存期（rPFS），具有良好的安全性。我们报告最终的总生存期（OS）分析和最新的安全性数据。患者和方法：PSMAfore （NCT04689828）是一项开放标签、国际3期试验。前列腺特异性膜抗原（PSMA）阳性的mCRPC患者在先前的ARPI中经历过疾病进展，并且是ARPI改变的候选患者，按1:1随机分配到177Lu-PSMA-617或ARPI改变为阿比特龙或恩杂鲁胺。在中央确认x线片进展后，允许从ARPI改变交叉到177Lu-PSMA-617。端点包括rPFS（主要）、OS（关键次要）和安全性（次要）。结果：患者被随机分配到177Lu-PSMA-617或ARPI改变组（n = 234）： 141/234名参与者（60.3%）被随机分配到ARPI改变交叉组（中央证实的放射学进展为75.4%）。177Lu-PSMA-617组的中位OS为24.48个月（95% CI 19.55-28.94）， ARPI变化组的中位OS为23.13个月（19.61-25.53）(风险比[HR] 0.91 [95% CI 0.72-1.14]；p = 0.20)基于意向治疗（ITT）原则；通过反向概率审查加权模型的交叉调整OS HR为0.59 （95% CI 0.38-0.91）。对于177Lu-PSMA-617与ARPI变化，暴露调整后≥3级和严重治疗后出现的不良事件发生率分别为60.8比85.1和32.5比49.9 / 100患者治疗年。227名参与者中有135人发生口干(59.5%；2/227≥3级)和62/227贫血(27.3%；14/227分级≥3)在177Lu-PSMA-617组。结论：基于ITT原则，OS分析未显示177Lu-PSMA-617组与ARPI组之间存在统计学差异；结果可能因交叉率高而混淆。177Lu-PSMA-617的安全性较好，未发现新的安全信号。
Final overall survival and safety analyses of the phase 3 PSMAfore trial of [177Lu]Lu-PSMA-617 versus change of androgen receptor pathway inhibitor in taxane-naive patients with metastatic castration-resistant prostate cancer.
Background: In PSMAfore, [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged radiographic progression-free survival (rPFS) in taxane-naive patients with metastatic castration-resistant prostate cancer (mCRPC), with a favourable safety profile, versus a change in androgen receptor pathway inhibitor (ARPI). We report the final overall survival (OS) analysis and updated safety data.
Patients and methods: PSMAfore (NCT04689828) was an open-label, international, phase 3 trial. Patients with prostate-specific membrane antigen (PSMA)-positive mCRPC who had experienced disease progression once on a previous ARPI and were candidates for ARPI change were randomized 1:1 to 177Lu-PSMA-617 or ARPI change to abiraterone or enzalutamide. Crossover from ARPI change to 177Lu-PSMA-617 was allowed after centrally confirmed radiographic progression. Endpoints included rPFS (primary), OS (key secondary), and safety (secondary).
Results: Patients were randomized to 177Lu-PSMA-617 or ARPI change (n = 234 each): 141/234 participants (60.3%) randomized to ARPI change crossed over (75.4% of those with centrally confirmed radiographic progression). The median OS was 24.48 months (95% CI 19.55-28.94) with 177Lu-PSMA-617 versus 23.13 (19.61-25.53) with ARPI change (hazard ratio [HR] 0.91 [95% CI 0.72-1.14]; p = 0.20) based on the intention-to-treat (ITT) principle; the crossover-adjusted OS HR by inverse probability of censoring weighting modelling was 0.59 (95% CI 0.38-0.91). For 177Lu-PSMA-617 versus ARPI change, exposure-adjusted incidences of grade ≥ 3 and serious treatment-emergent adverse events were 60.8 versus 85.1 and 32.5 versus 49.9 per 100 patient-treatment years, respectively. Dry mouth occurred in 135/227 participants (59.5%; 2/227 grade ≥ 3) and anaemia in 62/227 (27.3%; 14/227 grade ≥ 3) in the 177Lu-PSMA-617 arm.
Conclusions: OS analyses did not show a statistically significant difference between the 177Lu-PSMA-617 and ARPI arms based on the ITT principle; results were likely confounded by the high rate of crossover. The safety profile of 177Lu-PSMA-617 was favourable with no new safety signals identified.
期刊介绍：
Annals of Oncology, the official journal of the European Society for Medical Oncology and the Japanese Society of Medical Oncology, offers rapid and efficient peer-reviewed publications on innovative cancer treatments and translational research in oncology and precision medicine.
The journal primarily focuses on areas such as systemic anticancer therapy, with a specific emphasis on molecular targeted agents and new immune therapies. We also welcome randomized trials, including negative results, as well as top-level guidelines. Additionally, we encourage submissions in emerging fields that are crucial to personalized medicine, such as molecular pathology, bioinformatics, modern statistics, and biotechnologies. Manuscripts related to radiotherapy, surgery, and pediatrics will be considered if they demonstrate a clear interaction with any of the aforementioned fields or if they present groundbreaking findings.
Our international editorial board comprises renowned experts who are leaders in their respective fields. Through Annals of Oncology, we strive to provide the most effective communication on the dynamic and ever-evolving global oncology landscape.
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