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

Abstract

BackgroundWhile response rates to anti-PD1 therapy are low in unselected metastatic castration resistant prostate cancer (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 and clinically relevant subgroup's natural history and response to treatment. MethodsWe retrospectively identified patients at two academic institutions who had MMRd/MSI-high metastatic prostate cancer (PC). Clinical and pathologic characteristics at the time of diagnosis as well as 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. Results27 men with MMRd and/or MSI-high metastatic PC were identified. 13 (48%) men had M1 disease at diagnosis and 19 of 24 (79%) men that underwent prostate biopsy had a Gleason score �8. Median overall survival from time of metastasis was not reached (95% CI: 33.6-NR mos) after a median follow up of 33.6 mos (95% CI: 23.8-50.5 mos). Seventeen men received pembrolizumab, of which 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 the estimated PFS at 6 months was 64.1% (95% CI: 33.7%-83.4%). Of those

Novel therapies are changing treatment paradigms in metastatic prostate cancer

“…Radiographic responses occurred in 4 out of these 6 patients, and 5 patients were still on therapy for as long as 89 weeks [ 83 ]. Graham et al recently reported that of a total of 17 patients with dMMR and/or MSI-H mPC who received pembrolizumab, 53% had a ≥ 50% PSA reduction, and 87.5% of them remained on treatment at a median follow-up of 12 months [ 84 ]. Taking into account the above findings, microsatellite testing should be undertaken and pembrolizumab considered for patients with MSI-H status.…”

Integrating Germline Genetics Into Precision Oncology Practice in the Veterans Health Administration: Challenges and Opportunities

“…5,6 Individuals with a germline pathogenic variant in the MSH2, MLH1, MSH6, PMS2 or EPCAM genes (ie, Lynch syndrome) have tumors that are deficient in mismatch repair, and these tumors are responsive to inhibitors of the programmed death 1 (PD1) pathway. 7,8 In addition to changing treatment decisions, identifying pathogenic germline variants can have health, reproductive, and psychosocial implications for the patient and the patient's family members. 9,10 A pathogenic germline variant can imply disease risk for both the patient and his or her relatives.…”

The Genetic Complexity of Prostate Cancer

“…Considering their advanced stage, they respond relatively well to androgenic deprivation, but less so to taxanes once castration-resistant. Afflicted patients are a subgroup currently considered candidates and evaluated for anti-PD1 or anti-CTL4 immunotherapy [26,27]. On the germinal level, Pritchard et al [15] reported that, of 692 patients with mPCa, 12% showed deleterious germline mutations (1% involving MSH2, 1% MSH6 and 2% PMS2).…”