Clinical Outcomes of Patients With Metastatic Prostate Cancer With Microsatellite Instability Treated With Pembrolizumab.

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.

Duke Scholars

Author Tian Zhang Medicine, Medical Oncology