Clinical activity of pembrolizumab in metastatic prostate cancer with microsatellite instability high (MSI-H) detected by circulating tumor DNA

Abstract

To report a multi-institutional case series of patients with advanced microsatellite instability high (MSI-H) prostate adenocarcinoma identified with clinical cell-free DNA (cfDNA) next-generation sequencing (NGS) testing and treated with immune checkpoint inhibitors. Retrospective analysis of patients with metastatic castration-resistant prostate cancer (mCRPC) and MSI-H tumor detected by a commercially available cfDNA NGS assay Guardant360 (G360, Guardant Health) at eight different Academic Institutions in the USA, from September 2018 to April 2020. From a total of 14 MSI-H metastatic prostate cancer patients at participating centers, nine patients with mCRPC with 56% bone, 33% nodal, 11% liver and 11% soft-tissue metastases and a median PSA of 29.3 ng/dL, were treated with pembrolizumab after 2 lines of therapy for CRPC. The estimated median time on pembrolizumab was 9.9 (95% CI 1.0 to 18.8) months. Four patients (44%) achieved PSA50 after a median of 4 (3–12) weeks after treatment initiation including three patients with >99% PSA decline. Among the patients evaluable for radiographic response (n=5), the response rate was 60% with one complete response and two partial responses. Best response was observed after a median of 3.3 (1.4–7.6) months. At time of cut-off, four patients were still on pembrolizumab while four patients discontinued therapy due to progressive disease and one due to COVID-19 infection. Half of the patients with PSA50 had both MSI-H and pathogenic alterations in BRCA1 and BRCA2 in their G360 assays. The use of liquid biopsy to identify metastatic prostate cancer patients with MSI-H is feasible in clinical practice and may overcome some of the obstacles associated with prostate cancer tumor tissue testing. The robust activity of pembrolizumab in selected patients supports the generalized testing for MSI-H.

Patient-derived xenografts and organoids model therapy response in prostate cancer

“…Considering that MSI score/defective mismatch repair (dMMR) mechanism are used as biomarkers for PD-L1/PD-1 immunotherapy response 30 , 31 , and correlate with PD-L1 overexpression 32 , we assessed the expression level of immune-related markers and the overall immunomodulatory properties of PNPCa organoids. Compared to the normal tissue N1, all the PDXs, Org2, and the primary tumor showed a reduction of transcript abundance of the major histocompatibility complex (HLA-A and HLA-B) and of galectin-9, the main ligand of the inhibitory receptor Tim-3.…”

Detection of Microsatellite Instability: State of the Art and Future Applications in Circulating Tumour DNA (ctDNA)

“…A good overall agreement has been observed between conventional MSI tissue-based testing and newly developed ctDNA-based approaches [ 80 , 117 , 118 ]. This suggests that ctDNA-based MSI diagnosis could be performed as part of routine clinical practice to stratify patients with better prognosis that are likely to benefit from ICI, when tissue specimens are unavailable or scarce [ 117 , 118 , 122 ]. Through its minimally-invasive nature, liquid biopsy can be serially repeated in order to ensure real-time disease monitoring based on ctDNA kinetics.…”

Tumor Frameshift Mutation Proportion Predicts Response to Immunotherapy in Mismatch Repair-Deficient Prostate Cancer

“…However, only a small proportion of prostate cancers exhibit dMMR, with estimates ranging from 3% to 8% [11–15]. Thus, our best estimates of the efficacy of anti‐PD1 therapy in dMMR or microsatellite instability (MSI)–high prostate cancer are derived from retrospective case series with small numbers and short follow‐up [15–19]. More data are needed to define depth and durability of responses to anti‐PD1 therapy for men with dMMR prostate cancer.…”