Prostate-specific membrane antigen (PSMA) is a theranostic target for metastatic prostate cancer (PCa). However, castration-resistant PCa (CRPC) may lose PSMA expression after systemic therapy. Fibroblast activation protein (FAP), expressed by carcinoma-associated fibroblasts in various cancer types, including PCa, has the potential to be an alternative target. In this study, we evaluated FAP expression in CRPC to assess its potential, using PSMA as a comparison. Methods: FAP expression was assessed using immunohistochemistry in 116 CRPC tumors: 78 adenocarcinomas, 11 small cell carcinomas, and 27 anaplastic carcinomas. Correlation analysis between manual scoring and automated scoring was performed on 54 whole-slide sections of metastatic CRPC. Paired FAP and PSMA stains were assessed in tissue microarray cores of CRPC (n = 62), consisting of locally advanced CRPC (n = 9) and metastatic CRPC (n = 53). FAP and PSMA positivity was defined by an immunohistochemistry score of at least 10. To explore the correlation of PSMA and FAP inhibitor (FAPi) PET imaging and immunohistochemistry, a preliminary analysis of 4 patients included in a [⁶⁸Ga]-FAPi-46 imaging trial (NCT04457232) was conducted. Results: Manual and automated scoring of FAP yielded results with strong correlations. Overall, FAP expression in CRPC was notably lower than PSMA expression (median immunoscores, 14 vs. 72; P < 0.001). Different histologic subtypes of CRPC demonstrated distinct levels of PSMA expression, whereas their FAP expression levels were comparable. Among the 19 PSMA-negative tumors, 11 (58%) exhibited FAP positivity. FAP expression levels in lymph node metastases were significantly lower than those in nonnodal metastases (P = 0.021). Liver metastases showed significant enrichment of tumors with strong FAP expression compared with nonliver lesions (P = 0.016). In the 4 clinical trial patients, the biopsied metastatic lesions showed lower uptake on FAPi PET than on PSMA PET (median SUV_max, 9.6 vs. 14.5), consistent with FAP expression that was lower than PSMA expression in the corresponding tumor biopsy samples (median immunoscores, 30 vs. 160). Conclusion: Because of the low FAP expression levels in CRPC, the utility of FAPi PET imaging may be limited. Although FAPi PET imaging may be further tested in PSMA-negative CRPC, such as small cell carcinoma, other molecular imaging modalities should be evaluated as alternative choices.

前列腺特异性膜抗原 （PSMA） 是转移性前列腺癌 （PCa） 的治疗诊断靶标。然而，去势抵抗性 PCa （CRPC） 在全身治疗后可能会失去 PSMA 表达。成纤维细胞活化蛋白 （FAP） 由癌相关成纤维细胞在各种癌症类型（包括 PCa）中表达，有可能成为替代靶标。在这项研究中，我们使用 PSMA 作为比较，评估了 CRPC 中 FAP 的表达以评估其潜力。方法：使用免疫组织化学评估 116 例 CRPC 肿瘤中的 FAP 表达： 78 例腺癌、11 例小细胞癌和 27 例间变癌。对转移性 CRPC 的 54 个全玻片切片进行手动评分和自动评分之间的相关性分析。在 CRPC 的组织微阵列核心 （n = 62） 中评估配对的 FAP 和 PSMA 染色，由局部晚期 CRPC （n = 9） 和转移性 CRPC （n = 53） 组成。FAP 和 PSMA 阳性由免疫组化评分至少 10 定义。为了探讨 PSMA 和 FAP 抑制剂 （FAPi） PET 成像与免疫组化的相关性，对 [⁶⁸Ga]-FAPi-46 成像试验 （NCT04457232） 中纳入的 4 例患者进行了初步分析。结果：FAP 的手动和自动评分产生了具有很强相关性的结果。总体而言，CRPC 中的 FAP 表达显著低于 PSMA 表达（中位免疫评分，14 vs. 72;P < 0.001）。CRPC 的不同组织学亚型表现出不同水平的 PSMA 表达，而它们的 FAP 表达水平相当。在 19 例 PSMA 阴性肿瘤中，11 例 （58%） 表现出 FAP 阳性。 淋巴结转移中的 FAP 表达水平显著低于非结节转移中的 FAP 表达水平 （P = 0.021）。与非肝脏病灶相比，肝转移显示具有强 FAP 表达的肿瘤显着富集 （P = 0.016）。在 4 例临床试验患者中，活检的转移病灶显示 FAPi PET 的摄取率低于 PSMA PET （中位 SUV_最大值，9.6 vs. 14.5），这与相应肿瘤活检样本中 FAP 表达低于 PSMA 表达一致（中位免疫评分，30 vs. 160）。结论：由于 CRPC 中的 FAP 表达水平较低，因此 FAPi PET 成像的效用可能受到限制。尽管 FAPi PET 成像可以在 PSMA 阴性 CRPC（例如小细胞癌）中进一步检测，但应评估其他分子影像学检查方式作为替代选择。