Pembrolizumab, a PD-1 immune checkpoint inhibitor, was approved by the FDA in 2017 for metastatic MSI-H (microsatellite instability-high) and TMB-H (high tumor mutational burden) solid tumors, regardless of origin. We report a case of prostate cancer with rare SVC syndrome, MSI-H, and TMB-H identified through genomic profiling.

 

A 76-year-old man presented in October 2022 with three months of dysuria. Lab tests showed an elevated PSA of 99.7 ng/mL. A biopsy confirmed prostate adenocarcinoma (Gleason score 5+5). Imaging revealed bladder invasion and metastases to pelvic and para-aortic lymph nodes, with no bone involvement (cT3N1M1a). The patient started ADT with abiraterone for mHSPC. After two months, a CT scan showed regression of the primary tumor and metastatic lymph nodes, with PSA dropping to 1.63. Seven months later, PSA rose to 32.8, and new inguinal lymphadenopathy indicated progression to mCRPC (post-ARPi). Therapy thus shifted to docetaxel chemotherapy. After two cycles, PSA decreased to 1.86 but increased to 34.1 after the fourth cycle. The patient developed swelling in the right upper arm and mediastinal lymphadenopathy leading to SVC syndrome was found. Biopsy of the mediastinal lymph nodes confirmed neuroendocrine transdifferentiation. Due to rapid progression, genetic sequencing was ordered, revealing MSI-H and high TMB (29 Muts/Mb). Pembrolizumab therapy was initiated. Two months later, imaging showed significant reduction in SVC invasion(figure), and PSA dropped to 2.37, indicating partial response. Disease progressed after 6 cycles of treatment and the patient eventually passed away two years after diagnosis.

MSI-H and TMB-H cancers are eligible for pembrolizumab, but MSI-H is rare in prostate cancer (2-5% of cases), limiting its use in advanced prostate cancer. Larger trials have failed to show benefit of ICI-based therapies in unselected CRPC patients. MSI-H and TMB-H tumors often present at higher grades and may be somatically acquired during disease evolution. In this case, rapid progression and resistance to standard treatment led to the occurrence of mediastinal metastasis and SVC syndrome. Studies have shown some benefit from ICI therapy in MSI-H CRPC, with 6 of 11 patients having a >50% decline in PSA and 4 of 11 showing radiographic responses. This case showed a significant response to pembrolizumab therapy and highlights the importance of genetic sequencing in CRPC patients, particularly those progressing after ADT and ARPi.