TY - JOUR
T1 - Efficacy of Anti-PD-(L)1 Immunotherapy in Patients with DNA Mismatch Repair-deficient Metastatic Castration-resistant Prostate Cancer
AU - van Wilpe, Sandra
AU - Taha, Tarek
AU - Rothmann, Emily C.
AU - Altshuler, Ellery
AU - Park, Joe
AU - Ledet, Elisa M.
AU - Rothermundt, Christian
AU - Bergman, Andre M.
AU - Willemsen, Annelieke E.C.A.B.
AU - Tsantoulis, Petros
AU - Oldenburg, Jan
AU - Bernard-Tessier, Alice
AU - Fizazi, Karim
AU - Robbrecht, Debbie G.J.
AU - Bruijnen, Cheryl P.
AU - van der Hulle, Tom
AU - Antonarakis, Emmanuel S.
AU - Omlin, Aurelius
AU - Grönberg, Henrik
AU - Armstrong, Andrew J.
AU - Sartor, Oliver
AU - Sena, Laura A.
AU - Beltran, Himisha
AU - de Bono, Johann S.
AU - Mehra, Niven
N1 - Publisher Copyright:
Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.
PY - 2025/8/1
Y1 - 2025/8/1
N2 - BACKGROUND AND OBJECTIVE: Up to 5% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbour loss-of-function alterations in mismatch repair genes (dMMR) resulting in microsatellite instability (MSI-H). Data on the efficacy of immune checkpoint inhibitors (ICIs) in dMMR mCRPC are limited, and reimbursement for these agents is not universally available. METHODS: We performed an international, multicentre, retrospective study to investigate the efficacy of anti-PD-(L)1 monotherapy in dMMR mCRPC. dMMR was defined as MMR protein loss on immunohistochemistry (IHC), and/or a deleterious alteration in an MMR gene or MSI-H status according to polymerase chain reaction analysis or next-generation sequencing. The primary endpoint was progression-free survival (PFS). KEY FINDINGS AND LIMITATIONS: Between July 2016 and July 2024, 93 patients with a median age of 70 yr (range 46-90) started anti-PD-(L)1 treatment. Patients were classified as dMMR on the basis of IHC results (n = 37, 40%), genomic alterations in MMR genes (n = 55, 59%), and/or an MSI-H phenotype (n = 64, 69%). Among evaluable patients according to Response Evaluation Criteria in Solid Tumours v1.1, the objective response rate was 46% (n = 84; 95% confidence interval [CI] 35-58%). A prostate-specific antigen decline ≥50% was observed in 60% of evaluable patients (n = 68; 95% CI 48-72%). Median PFS across the entire cohort was 7.7 mo (95% CI 5.3-12.4), with 1-yr, 2-yr, and 3-yr PFS rates of 39%, 27%, and 26%, respectively. Median overall survival was 27.0 mo (95% CI 17.7-43.5). PFS was significantly longer for patients with positive dMMR status on two or more tests than for patients with just one positive dMMR test. CONCLUSIONS AND CLINICAL IMPLICATIONS: These data confirm the efficacy of anti-PD-(L)1 therapy in patients with dMMR mCRPC and warrant consideration of reimbursement for anti-PD-(L)1 agents in dMMR mCRPC by health authorities.
AB - BACKGROUND AND OBJECTIVE: Up to 5% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbour loss-of-function alterations in mismatch repair genes (dMMR) resulting in microsatellite instability (MSI-H). Data on the efficacy of immune checkpoint inhibitors (ICIs) in dMMR mCRPC are limited, and reimbursement for these agents is not universally available. METHODS: We performed an international, multicentre, retrospective study to investigate the efficacy of anti-PD-(L)1 monotherapy in dMMR mCRPC. dMMR was defined as MMR protein loss on immunohistochemistry (IHC), and/or a deleterious alteration in an MMR gene or MSI-H status according to polymerase chain reaction analysis or next-generation sequencing. The primary endpoint was progression-free survival (PFS). KEY FINDINGS AND LIMITATIONS: Between July 2016 and July 2024, 93 patients with a median age of 70 yr (range 46-90) started anti-PD-(L)1 treatment. Patients were classified as dMMR on the basis of IHC results (n = 37, 40%), genomic alterations in MMR genes (n = 55, 59%), and/or an MSI-H phenotype (n = 64, 69%). Among evaluable patients according to Response Evaluation Criteria in Solid Tumours v1.1, the objective response rate was 46% (n = 84; 95% confidence interval [CI] 35-58%). A prostate-specific antigen decline ≥50% was observed in 60% of evaluable patients (n = 68; 95% CI 48-72%). Median PFS across the entire cohort was 7.7 mo (95% CI 5.3-12.4), with 1-yr, 2-yr, and 3-yr PFS rates of 39%, 27%, and 26%, respectively. Median overall survival was 27.0 mo (95% CI 17.7-43.5). PFS was significantly longer for patients with positive dMMR status on two or more tests than for patients with just one positive dMMR test. CONCLUSIONS AND CLINICAL IMPLICATIONS: These data confirm the efficacy of anti-PD-(L)1 therapy in patients with dMMR mCRPC and warrant consideration of reimbursement for anti-PD-(L)1 agents in dMMR mCRPC by health authorities.
KW - Castration-resistant prostate cancer
KW - Immune checkpoint inhibitors
KW - Microsatellite instability
KW - Mismatch repair deficiency
UR - https://www.scopus.com/pages/publications/105016569968
UR - https://www.scopus.com/pages/publications/105016569968#tab=citedBy
U2 - 10.1016/j.euo.2025.04.016
DO - 10.1016/j.euo.2025.04.016
M3 - Article
C2 - 40651931
AN - SCOPUS:105016569968
SN - 2588-9311
VL - 8
SP - 1020
EP - 1029
JO - European Urology Oncology
JF - European Urology Oncology
IS - 4
ER -
