<p><strong> </strong><strong>In patients with MMR deficient or MSI-H mCRPC, clinicians should offer pembrolizumab. (<em>Moderate Recommendation; Evidence Level: Grade C</em>)</strong></p>
Discussion
Discussion
<p>Unlike the other major urologic neoplasms such as renal cell and urothelial cancers where next generation immunotherapy agents (check point inhibitors and anti-CTLA-4 agents) have demonstrated meaningful activity, there has been limited evidence of the utility of these therapies in mCRPC.</p>
<p>The MMR system is a post-replicative, single-strand repair mechanism that recognizes and reverses DNA base mismatches and insertions/deletions. Compromised MMR results in MSI and a hypermutator phenotype that has been associated with chemotherapy resistance but immunotherapy sensitivity.<sup>143</sup></p>
<p>In a case series of 1,033 patients with advanced prostate cancer 3.1% had an MSI-H/dMMR prostate cancer, with more than half of those treated with anti PD-1 therapy responding to treatment having a >50% decline in PSA.<sup>144</sup></p>
<p>Until recently assessment of MSI status was a tissue-based assay and is still optimally done with archival or fresh tissue. Recent evidence suggests that cell-free DNA sequencing methods may allow MSI status to be determined with liquid biopsies.</p>
<p>In May 2017, the FDA approved pembrolizumab for patients with any metastatic MSI-H or dMMR histology that have progressed following prior treatment, and who have no satisfactory alternative treatment options.<sup>41</sup></p>