Mismatch repair deficiency in metastatic prostate cancer (PC): Response to PD-1 blockade and standard therapies.

Abstract

194 Background: While response rates to anti-PD1 therapy are low in unselected metastatic castration resistant PC (mCRPC) patients, those with inactivating mutations in mismatch repair (MMR) genes (i.e. MMR deficiency; MMRd) or microsatellite instability (MSI) are thought likely to respond favorably. To date, there is limited published data on this biologically distinct, yet clinically relevant subgroup’s natural history and response to treatment. Methods: We retrospectively identified patients at two academic institutions who had MMRd/MSI-high metastatic PC. Clinical and pathologic characteristics at time of diagnosis and response to standard therapies and immune checkpoint therapy were abstracted. Descriptive statistics, including PSA50 response (≥50% decline in PSA from baseline) and clinical/radiographic progression free survival (PFS), are reported. Results: 28 men with MMRd and/or MSI-high metastatic PC were identified. 14 (50%) men had M1 disease at diagnosis and 19 (76%) of 25 men that underwent prostate biopsy had a Gleason score (GS) ≥8. Median overall survival from time of metastasis was not reached (95% CI: 33.7-NR mos) after median follow up of 43.6 mos (95% CI: 25.8-65.2 mos). PSA responses to standard therapies were similar to historic controls (Table). 17 patients received pembrolizumab and 15 had PSA response data available. PSA50 responses to pembrolizumab occurred in 8 (53%) men. Median PFS was not reached (95% CI: 1.87-NR mos) and estimated PFS at 6 months was 64.1% (95% CI: 33.7%-83.4%). Of those who had a PSA50 response, 7 (87.5%) remain on treatment without evidence of progression. Conclusions: MMRd PC is associated with high GS and advanced disease at presentation. Response rates to standard therapies are comparable to those reported in unselected patients and response rate to checkpoint blockade is high.[Table: see text]