INTRODUCTION AND OBJECTIVE: Prostate cancers with high microsatellite instability/deficient mismatch repair (MSI-H/dMMR) and high tumor mutational burden (TMB-H) are rare but recognized as molecular subgroups with therapeutic implications. Patients harboring either of these genomic features are candidates for treatment with immunotherapy (IO) based on tumor agnostic approvals. Given the potential for different underlying biology, we aimed to compare clinical outcomes in patients with MSI-H/dMMR and TMB-H prostate cancer treated with IO. METHODS: We identified men with prostate cancer who underwent paired tumorenormal genomic profiling with MSK-IMPACT, a targeted exome sequencing panel. MSI-H/dMMR prostate cancer was defined as MSIsensor score !10 or MSIsensor score of !3 and <10 with evidence of a deleterious somatic or germline alteration in a mismatch repair gene (MSH6, MSH2, MLH1, or PMS2). TMB-H was defined as !10 in the absence of microsatellite instability. Response to IO was defined as a 50% decrease in PSA (PSA 50 ). Median time to IO discontinuation was estimated using the Kaplan-Meier method. RESULTS: Of 2,351 men with prostate cancer who underwent MSK-IMPACT testing between 2/2014 and 2/2021, 62 (2.6%) were identified as having MSI-H/dMMR prostate cancer and 29 (1.2%) as having TMB-H. Of the 62 patients with MSI-H/dMMR prostate cancer, 29 (32%) were treated with IO and 26 had metastatic castration resistant disease and evaluable PSA levels. PSA 50 was observed in 65% (17/26); no significant difference in response between MSI-H/ dMMR and TMB-H patients was observed. The median time to IO discontinuation in patients with MSI-H/dMMR and TMB-H tumors was 20 (IQR: 10e107) and 12 (IQR: 9e15) weeks, respectively. At a median follow-up of 90 weeks, 35% (7/20) of MSI-H/dMMR and 33% (2/6) of TMB-H tumors were still on IO. MSIsensor scores and TMB were not significantly different between IO responders and nonresponders. CONCLUSIONS: MSI-H/dMMR and TMB-H prostate cancers are rare but up to two thirds of such patients respond to IO with many durable responses. MSIsensor score and TMB were not predictive of response to IO in these molecularly defined populations. Other clinical and genomic factors are being investigated to identify biomarkers to guide treatment selection.
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