Clinical Features and Therapeutic Outcomes in Men with Advanced Prostate Cancer and DNA Mismatch Repair Gene Mutations

Mismatch repair (MMR) gene mutations are rare in prostate cancer, and their histological and clinical characteristics are largely unknown. We conducted a retrospective study to explore disease characteristics and treatment outcomes of men with metastatic prostate cancer harboring germline and/or somatic MMR mutations detected using clinical-grade genomic assays. Thirteen patients with a deleterious MMR gene mutation were identified. Median age was 64 yr, 75% had grade group 5 (Gleason sum 9 or 10), 23% had intraductal histology, 46% had metastatic disease at initial diagnosis, and 31% had visceral metastases. Most patients (46%) had MSH6 mutations, 73% demonstrated microsatellite instability, and median tumor mutational load was 18/Mb (range, 3–165 mutations/Mb). Surprisingly, responses to standard hormonal therapies were very durable (median progression-free survival [PFS] of 67 mo to initial androgen deprivation and median PFS of 26 mo to abiraterone/enzalutamide). Two of four men receiving PD-1 inhibitors achieved a ≥50% prostate-specific antigen response at 12 wk, with a median PFS duration in these four men of 9 mo. Despite aggressive clinical and pathological features, patients with MMR-mutated advanced prostate cancer appear to have particular sensitivity to hormonal therapies, as well as anecdotal responses to PD-1 inhibitors. Certain histological features (grade group 5, intraductal carcinoma) should prompt evaluation for MMR deficiency. These data are only hypothesis generating. Prostate cancers with mismatch repair gene mutations have aggressive clinical and pathological features; however, these are very sensitive to standard and novel hormonal therapies, and also demonstrate anecdotal sensitivity to PD-1 inhibitors such as pembrolizumab. Despite aggressive clinicopathological features, mismatch repair (MMR)-mutated advanced prostate cancers are exquisitely responsive to standard and next-generation hormonal therapies, and also demonstrate anecdotal sensitivity to PD-1 inhibitors. Moreover, the presence of certain histological features (Gleason sum 9 or 10, and intraductal carcinoma) should prompt genomic evaluation of MMR deficiency, which is an actionable finding given the Food and Drug Administration's approval of pembrolizumab in this context.