Efficacy of radiotherapy in pembrolizumab-resistant microsatellite instability–high prostate cancer: a two-case series

Background Microsatellite instability-high (MSI-H) prostate cancer (PCa) is a rare molecular subtype characterized by aggressive behavior and resistance to conventional therapies. Pembrolizumab, a PD-1 inhibitor, has demonstrated substantial clinical efficacy in MSI-H PCa; however, optimal therapeutic strategies for patients who experience disease progression on pembrolizumab remain undefined. Case presentation: We describe two patients with MSI-H PCa who exhibited disease progression during pembrolizumab treatment. Both patients initially presented with gross hematuria and large prostate tumors invading the bladder. They demonstrated resistance to androgen deprivation therapy, androgen receptor signal inhibitors, and chemotherapy. Comprehensive genome profiling revealed MSH2 and MSH6 homozygous deletion in both cases, confirming MSI-H status. Despite pembrolizumab initiation, their disease progressed, and subsequent systemic therapies showed no effect. Owing to persistent gross hematuria and progressive local invasion, both patients finally required urinary diversion procedures. Following surgery, radiotherapy was administered to the tumor, resulting in rapid decrease of PSA and marked radiographic tumor regression. At the latest follow-up, both patients maintained durable disease control for 10 and 8 months after radiotherapy, respectively, without evidence of recurrence. Conclusions Although pembrolizumab has been reported to achieve deep and durable responses in some patients with MSI-H PCa, others experience disease progression and require multimodal management. These cases suggest that radiotherapy may play a critical therapeutic role in pembrolizumab-resistant MSI-H PCa.