[¹⁷⁷Lu]Lu-PSMA-617 was approved by the U.S. Food and Drug Administration for patients with prostate-specific membrane antigen (PSMA)–positive metastatic castration-resistant prostate cancer (mCRPC). Since the time of regulatory approval, however, real-world data have been lacking. This study investigated the efficacy, safety, and outcome predictors of [¹⁷⁷Lu]Lu-PSMA-617 at a major U.S. academic center. Methods: Patients with mCRPC who received [¹⁷⁷Lu]Lu-PSMA-617 at the Johns Hopkins Hospital outside clinical trials were screened for inclusion. Patients who underwent [¹⁷⁷Lu]Lu-PSMA-617 and had available outcome data were included in this study. Outcome data included prostate-specific antigen (PSA) response (≥50% decline), PSA progression-free survival (PFS), and overall survival (OS). Toxicity data were evaluated according to the Common Terminology Criteria for Adverse Events version 5.03. The study tested the association of baseline circulating tumor DNA mutational status in homologous recombination repair, PI3K alteration pathway, and aggressive-variant prostate cancer–associated genes with treatment outcome. Baseline PSMA PET/CT images were analyzed using SelectPSMA, an artificial intelligence algorithm, to predict treatment outcome. Associations with the observed treatment outcome were evaluated. Results: All 76 patients with PSMA-positive mCRPC who received [¹⁷⁷Lu]Lu-PSMA-617 met the inclusion criteria. A PSA response was achieved in 30 of 74 (41%) patients. The median PSA PFS was 4.1 mo (95% CI, 2.0–6.2 mo), and the median OS was 13.7 mo (95% CI, 11.3–16.1 mo). Anemia of grade 3 or greater, thrombocytopenia, and neutropenia were observed in 9 (12%), 3 (4%), and 1 (1%), respectively, of 76 patients. Transient xerostomia was observed in 23 (28%) patients. The presence of aggressive-variant prostate cancer–associated genes was associated with a shorter PSA PFS (median, 1.3 vs. 6.3 mo; P = 0.040). No other associations were observed between circulating tumor DNA mutational status and treatment outcomes. Eighteen of 71 (25%) patients classified by SelectPSMA as nonresponders had significantly lower rates of PSA response than patients classified as likely responders (6% vs. 51%; P < 0.001), a shorter PSA PFS (median, 1.3 vs. 6.3 mo; P < 0.001), and a shorter OS (median, 6.3 vs. 14.5 mo; P = 0.046). Conclusion: [¹⁷⁷Lu]Lu-PSMA-617 offered in a real-world setting after regulatory approval in the United States demonstrated antitumor activity and a favorable toxicity profile. Artificial-intelligence–based analysis of baseline PSMA PET/CT images may improve patient selection. Validation of these findings on larger cohorts is warranted.

[¹⁷⁷Lu]Lu-PSMA-617 已被美国食品药品监督管理局批准用于前列腺特异性膜抗原 （PSMA） 阳性转移性去势抵抗性前列腺癌 （mCRPC） 患者。然而，自监管部门批准以来，一直缺乏真实世界的数据。本研究在美国一家主要学术中心调查了 [¹⁷⁷Lu]Lu-PSMA-617 的疗效、安全性和结果预测因子。方法：筛选在临床试验之外在约翰霍普金斯医院接受 [¹⁷⁷Lu]Lu-PSMA-617 治疗的 mCRPC 患者。本研究纳入接受 [¹⁷⁷Lu]Lu-PSMA-617 并有可用结果数据的患者。结局数据包括前列腺特异性抗原 （PSA） 反应 （下降 ≥50%） 、 PSA 无进展生存期 （PFS） 和总生存期 （OS）。根据不良事件通用术语标准 5.03 版评估毒性数据。该研究测试了同源重组修复、PI3K 改变途径和侵袭性变异前列腺癌相关基因中基线循环肿瘤 DNA 突变状态与治疗结果的关联。使用人工智能算法 SelectPSMA 分析基线 PSMA PET/CT 图像，以预测治疗结果。评估与观察到的治疗结果的关联。结果：所有 76 例接受 [¹⁷⁷Lu]Lu-PSMA-617 治疗的 PSMA 阳性 mCRPC 患者均符合纳入标准。74 例患者中有 30 例 （41%） 达到 PSA 反应。中位 PSA PFS 为 4.1 个月 （95% CI，2.0-6.2 个月），中位 OS 为 13.7 个月 （95% CI，11.3-16.1 个月）。 在 76 例患者中，分别有 9 例 （12%） 、 3 例 （4%） 和 1 例 （1%） 观察到 3 级或以上的贫血、血小板减少症和中性粒细胞减少症。在 23 例 （28%） 患者中观察到短暂的口干症。侵袭性变异前列腺癌相关基因的存在与较短的 PSA PFS 相关 （中位数，1.3 vs. 6.3 个月;P = 0.040）。未观察到循环肿瘤 DNA 突变状态与治疗结果之间的其他关联。被 SelectPSMA 归类为无反应者的 71 例患者中有 18 例 （25%） 的 PSA 反应率显著低于被归类为可能反应者的患者（6% 对 51%;P < 0.001），较短的 PSA PFS（中位数，1.3 vs. 6.3 个月;P < 0.001），以及较短的 OS（中位数，6.3 vs. 14.5 个月;P = 0.046）。结论：在美国监管部门批准后，[¹⁷⁷Lu]Lu-PSMA-617 在现实世界中提供，显示出抗肿瘤活性和良好的毒性特征。基于人工智能的基线 PSMA PET/CT 图像分析可能会改善患者的选择。有必要在更大的队列中验证这些发现。