Lambert Nicholas, Moore Casey, Klavon Julia, Arafat Waddah, Wang Jue, Zhang Tian, Courtney Kevin
Department of Internal Medicine, Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX; University of Texas Southwestern Harold C. Simmons Comprehensive Cancer Center, Dallas, TX.
University of Texas Southwestern Harold C. Simmons Comprehensive Cancer Center, Dallas, TX.
Clin Genitourin Cancer. 2025 Oct;23(5):102384. doi: 10.1016/j.clgc.2025.102384. Epub 2025 Jun 14.
MSI-H prostate cancer is rarely encountered in clinical practice. When it is identified, pembrolizumab is a standard of care therapeutic option in the metastatic castration-resistant setting based on KEYNOTE-158, which included very few prostate cancer patients. A few previously published case series have shown encouraging clinical outcomes for patients with MSI-H mCRPC treated with pembrolizumab, however, there is still a paucity of real-world data. Here we report an institutional case series of 13 patients with MSI-H metastatic prostate cancer identified by next generation sequencing of tumor tissue or ctDNA who were treated with pembrolizumab between October 2019 and December 2024. 12 patients had mCRPC and one patient had mCSPC. Among the mCRPC cohort, patients had received on average 2.7 prior lines of therapy and had a median PSA of 19.8 ng/mL. Sites of disease involvement were nodal (83.3%), bone (75%), bladder (25%), liver (16.7%), and rectum (8.3%). 9 of the 12 (75%) patients with mCRPC achieved PSA50 while on therapy, including 7 patients (58.3%) who achieved a complete biochemical response with undetectable PSA. Radiographically, overall response rate among the 7 patients with evaluable disease by RECIST 1.1 or PCWG3 was 57.1% with 2 complete responses and 2 partial responses. As of the data cutoff, 7 patients were alive, and 2 patients remained on treatment. After a median follow-up period of 14.4 months, median PFS and OS were not reached. The mCSPC patient, who is reported separately, achieved a complete biochemical and radiographic response. Treatment with pembrolizumab led to a significant rate of biochemical and radiographic response in a heavily pre-treated cohort of MSI-H metastatic prostate cancer patients, and multiple patients achieved a durable complete response. Somatic mutation testing results were analyzed for all patients. Out of 7 patients who achieved a complete biochemical response, 6 had a homologous recombination repair (HRR) gene mutation, and all 3 patients with PTCH1 mutations had a complete biochemical response, raising questions regarding potential predictive biomarkers for pembrolizumab therapy. The unique cases of the patient with mCSPC and another patient who was re-challenged with pembrolizumab after late progression are reported and highlight the need for more investigation into the optimal sequencing and duration of pembrolizumab in MSI-H prostate cancer, respectively.
微卫星高度不稳定（MSI-H）前列腺癌在临床实践中很少见。当确诊后，基于KEYNOTE-158研究（该研究纳入的前列腺癌患者极少），帕博利珠单抗是转移性去势抵抗性前列腺癌标准的治疗选择。一些先前发表的病例系列显示，帕博利珠单抗治疗MSI-H转移性去势抵抗性前列腺癌患者的临床结果令人鼓舞，然而，真实世界的数据仍然匮乏。在此，我们报告了一个机构性病例系列，共13例MSI-H转移性前列腺癌患者，这些患者通过肿瘤组织或循环肿瘤DNA（ctDNA）的下一代测序得以确诊，并于2019年10月至2024年12月期间接受了帕博利珠单抗治疗。12例患者患有转移性去势抵抗性前列腺癌（mCRPC），1例患者患有转移性去势敏感性前列腺癌（mCSPC）。在mCRPC队列中，患者平均接受了2.7线先前治疗，前列腺特异性抗原（PSA）中位数为19.8 ng/mL。疾病累及部位包括淋巴结（83.3%）、骨（75%）、膀胱（25%）、肝（16.7%）和直肠（8.3%）。12例mCRPC患者中有9例（75%）在治疗期间达到了PSA下降50%，其中7例（58.3%）实现了完全生化缓解，PSA检测不到。影像学方面，根据实体瘤疗效评价标准（RECIST）1.1或前列腺癌工作组（PCWG3）标准，7例可评估疾病的患者总体缓解率为57.1%，其中2例完全缓解，2例部分缓解。截至数据截止时，7例患者存活，2例患者仍在接受治疗。中位随访期为14.4个月后，中位无进展生存期（PFS）和总生存期（OS）均未达到。单独报告的mCSPC患者实现了完全生化和影像学缓解。在经过大量前期治疗的MSI-H转移性前列腺癌患者队列中，帕博利珠单抗治疗导致了显著的生化和影像学缓解率，并且多名患者实现了持久的完全缓解。对所有患者的体细胞突变检测结果进行了分析。在7例实现完全生化缓解的患者中，6例存在同源重组修复（HRR）基因突变，所有3例携带PTCH1突变的患者均实现了完全生化缓解，这引发了关于帕博利珠单抗治疗潜在预测生物标志物的疑问。报告了mCSPC患者以及另1例在疾病晚期进展后再次接受帕博利珠单抗治疗患者的独特病例，分别凸显了对MSI-H前列腺癌中帕博利珠单抗的最佳给药顺序和持续时间进行更多研究的必要性。
