Fizazi K, Chi K N, Shore N D, Herrmann K, de Bono J S, Castellano D, Piulats J M, Fléchon A, Wei X X, Mahammedi H, Roubaud G, Fleming M, Haas T, Ghebremariam S, Kreisl T N, Rajagopalan S, Sartor O, Morris M J
Institut Gustave Roussy and Centre Oscar Lambret, Université Paris-Saclay, Villejuif, France.
BC Cancer, Vancouver, BC, Canada.
Ann Oncol. 2025 Jul 16. doi: 10.1016/j.annonc.2025.07.003.
In PSMAfore, [Lu]Lu-PSMA-617 (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.
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 Lu-PSMA-617 or ARPI change to abiraterone or enzalutamide. Crossover from ARPI change to Lu-PSMA-617 was allowed after centrally confirmed radiographic progression. Endpoints included rPFS (primary), OS (key secondary), and safety (secondary).
Patients were randomized to 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 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 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 Lu-PSMA-617 arm.
OS analyses did not show a statistically significant difference between the 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 Lu-PSMA-617 was favourable with no new safety signals identified.
在PSMAfore研究中，与更换雄激素受体通路抑制剂（ARPI）相比，[镥]镥-PSMA-617（Lu-PSMA-617）延长了初治转移性去势抵抗性前列腺癌（mCRPC）患者的影像学无进展生存期（rPFS），且安全性良好。我们报告最终的总生存期（OS）分析和更新的安全性数据。
PSMAfore（NCT04689828）是一项开放标签的国际3期试验。前列腺特异性膜抗原（PSMA）阳性的mCRPC患者，既往曾接受过一次ARPI治疗且疾病进展，适合更换ARPI，按1:1随机分为Lu-PSMA-617组或更换为阿比特龙或恩杂鲁胺的ARPI组。经中心确认影像学进展后，允许从更换ARPI组交叉至Lu-PSMA-617组。终点包括rPFS（主要终点）、OS（关键次要终点）和安全性（次要终点）。
患者被随机分为Lu-PSMA-617组或更换ARPI组（每组n = 234）：随机分配至更换ARPI组的141/234名参与者（60.3%）发生了交叉（在经中心确认影像学进展的患者中占75.4%）。基于意向性分析（ITT）原则，Lu-PSMA-617组的中位OS为24.48个月（95%CI 19.55 - 28.94），更换ARPI组为23.13个月（19.61 - 25.53）（风险比[HR] 0.91 [95%CI 0.72 - 1.14]；p = 0.20）；通过逆概率删失加权模型进行交叉调整后的OS HR为0.59（95%CI 0.38 - 0.91）。与更换ARPI相比，Lu-PSMA-617组≥3级和严重治疗中出现的不良事件的暴露调整发病率分别为每100患者治疗年60.8例和85.1例，以及32.5例和49.9例。Lu-PSMA-617组中，135/227名参与者（59.5%；2/227例≥3级）出现口干，62/227名（27.3%；14/227例≥3级）出现贫血。
基于ITT原则，OS分析未显示Lu-PSMA-617组和ARPI组之间存在统计学显著差异；结果可能因高交叉率而混淆。Lu-PSMA-617的安全性良好，未发现新的安全信号。
