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

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

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Competing interests: PB has a consulting/advisory role (Institution) with Exelixis, Caris, Bayer, Janssen, EMD/Serono, Pfizer, Astellas, Dendreon, Clovis and Sanofi. Contracted Research (Institution) from Seattle Genetics, BlueEarth Diagnostics, Nektar, AstraZeneca and Seattle Genetics. NA has a consulting/advisory role with Astellas, Astra Zeneca, Bayer, Bristol Myers Squibb, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Janssen, Merck, Nektar, Novartis, Pfizer, Pharmacyclics and Seattle Genetics. Contracted Research (Instituion) from Astra Zeneca, Bavarian Nordic, Bayer, BN immunotherapeutics, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Glaxo Smith Kline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda and Tracon. HB has a consulting/advisory role with Endocyte, Celgene, Guardant360, Tracon. Honoraria: SirTex, Bayer. Speaker Bureau: Guardant360. LK is employee of Guardant Health. OS has a consulting/advisory role with AAA, Astellas, Astrazeneca, Bayer, Blue Earth Diagnostics, EMD Serono, Endocyte, Pfizer, Progenics, Sanofi, Invitae, Merck, Novartis, Janseen, Constellation, Dendreon, BMS, Bravarin Nordic, Clovis, Myriad, Noria Therapeutics, Noxopharm, Point Biopharma and Tenebio. Contracted Research from Innocrin, Sotio. He also serves as consultant on NCI Scientific Board Counselors and is a cochairman of GU Committee at NRG.