Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade

Abstract

The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab is approved by the US Food and Drug Administration for the treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors, but the prevalence of MSI-H/dMMR prostate cancer and the clinical utility of immune checkpoint blockade in this disease subset are unknown. OBJECTIVE To define the prevalence of MSI-H/dMMR prostate cancer and the clinical benefit of anti-PD-1/programmed cell death 1 ligand 1 (PD-L1) therapy in this molecularly defined population. DESIGN, SETTING, AND PARTICIPANTS In this case series, 1551 tumors from 1346 patients with prostate cancer undergoing treatment at Memorial Sloan Kettering Cancer Center were prospectively analyzed using a targeted sequencing assay from January 1, 2015, through January 31, 2018. Patients had a diagnosis of prostate cancer and consented to tumor molecular profiling when a tumor biopsy was planned or archival tissue was available. For each patient, clinical outcomes were reported, with follow-up until May 31, 2018. MAIN OUTCOMES AND MEASURES Tumor mutation burden and MSIsensor score, a quantitative measure of MSI, were calculated. Mutational signature analysis and immunohistochemistry for MMR protein expression were performed in select cases. RESULTS Among the 1033 patients who had adequate tumor quality for MSIsensor analysis (mean [SD] age, 65.6 [9.3] years), 32 (3.1%) had MSI-H/dMMR prostate cancer. Twenty-three of 1033 patients (2.2%) had tumors with high MSIsensor scores, and an additional 9 had indeterminate scores with evidence of dMMR. Seven of the 32 MSI-H/dMMR patients (21.9%) had a pathogenic germline mutation in a Lynch syndrome-associated gene. Six patients had more than 1 tumor analyzed, 2 of whom displayed an acquired MSI-H phenotype later in their disease course. Eleven patients with MSI-H/dMMR castration-resistant prostate cancer received anti-PD-1/PD-L1 therapy. Six of these (54.5%) had a greater than 50% decline in prostate-specific antigen levels, 4 of whom had radiographic responses. As of May 2018, 5 of the 6 responders (5 of 11 total [45.5%]) were still on therapy for as long as 89 weeks. CONCLUSIONS AND RELEVANCE The MSI-H/dMMR molecular phenotype is uncommon yet therapeutically meaningful in prostate cancer and can be somatically acquired during disease evolution. Given the potential for durable responses to anti-PD-1/PD-L1 therapy, these findings support the use of prospective tumor sequencing to screen all patients with advanced prostate cancer for MSI-H/dMMR. Because not all patients with the MSI-H/dMMR phenotype respond, further studies should explore mechanisms of resistance.

Pembrolizumab in men with heavily treated metastatic castrate‐resistant prostate cancer

“…Eleven patients with MSI‐H/dMMR mCRPC received anti–PD‐1/PD‐L1 therapy. Six of these men (54.5%) had a ≥50% decline in PSA levels, four of whom had radiographic responses . Together, these data support the clinical activity of PD‐1 blockade in selected men with mCRPC and suggest that subsets of men with MSI‐high and those with concurrent therapy with enzalutamide may have greater activity.…”

Pembrolizumab for a patient with metastatic castration‐resistant prostate cancer with microsatellite instability‐high

“…MSI‐high prostate cancer is uncommon, and its rarity seems to hamper the spread of immune checkpoint inhibitor therapy for CRPC. Abida et al . reported the prevalence of MSI‐high in patients with prostate cancer at the MSKCC.…”

“…In their report, 1346 patients underwent paired tumor and germline sequencing, and only 32 of 1033 (3.1%) had MSI‐high or MMR‐deficient disease, among whom seven (21.9%) carried a germline mutation in the MMR genes . Among these patients, six patients had more than one tumor analyzed, and two of these patients (33.3%) showed an acquired MSI‐high phenotype later in their disease course . When an archive specimen did not show MSI‐high status, we may need to obtain fresh tissues from the metastatic sites.…”

Extreme responses to immune checkpoint blockade following bipolar androgen therapy and enzalutamide in patients with metastatic castration resistant prostate cancer

“…However, a subset of patients with mCRPC do derive significant benefit from immune checkpoint inhibitors 5 . These immunologically responsive tumors may harbor homologous recombination (HR), DNA repair gene mutations, 6 inactivating CDK12 mutations, 7,8 or mismatch repair deficiency 9,10 …”

“…5 These immunologically responsive tumors may harbor homologous recombination (HR), DNA repair gene mutations, 6 inactivating CDK12 mutations, 7,8 or mismatch repair deficiency. 9,10 Recently, combination therapy has been studied as a means to improve the clinical response rate of patients with prostate cancer to immunotherapy. For instance, the addition of pembrolizumab at the time of progression on enzalutamide showed promising preliminary activity in one small study.…”