Efficacy of Anti-PD-(L)1 Immunotherapy in Patients with DNA Mismatch Repair-deficient Metastatic Castration-resistant Prostate Cancer

Sandra van Wilpe; Tarek Taha; Emily C. Rothmann; Ellery Altshuler; Joe Park; Elisa M. Ledet; Christian Rothermundt; Andre M. Bergman; Annelieke E.C.A.B. Willemsen; Petros Tsantoulis; Jan Oldenburg; Alice Bernard-Tessier; Karim Fizazi; Debbie G.J. Robbrecht; Cheryl P. Bruijnen; Tom van der Hulle; Emmanuel S. Antonarakis; Aurelius Omlin; Henrik Grönberg; Andrew J. Armstrong; Oliver Sartor; Laura A. Sena; Himisha Beltran; Johann S. de Bono; Niven Mehra

doi:10.1016/j.euo.2025.04.016

Efficacy of Anti-PD-(L)1 Immunotherapy in Patients with DNA Mismatch Repair-deficient Metastatic Castration-resistant Prostate Cancer

Sandra van Wilpe^*
, Tarek Taha
, Emily C. Rothmann
, Ellery Altshuler
, Joe Park
, Elisa M. Ledet
, Christian Rothermundt
, Andre M. Bergman
, Annelieke E.C.A.B. Willemsen
, Petros Tsantoulis
, Jan Oldenburg
, Alice Bernard-Tessier
, Karim Fizazi
, Debbie G.J. Robbrecht
, Cheryl P. Bruijnen
, Tom van der Hulle
, Emmanuel S. Antonarakis
, Aurelius Omlin
, Henrik Grönberg
, Andrew J. Armstrong

Oliver Sartor, Laura A. Sena, Himisha Beltran, Johann S. de Bono, Niven Mehra

^*Corresponding author for this work

Medical Oncology

Radboud University Medical Center
Institute of Cancer Research (ICR), London
Dana-Farber Cancer Institute
Johns Hopkins University
Duke University
Tulane University
Cantonal Hospital St. Gallen
Netherlands Cancer Institute
Tergooi Medisch Centrum
University of Geneva
Akershus University Hospital
Institut Gustave Roussy
Utrecht University
Leiden University
University of Minnesota Twin Cities
University of Zurich
Karolinska Institutet

Research output: Contribution to journal › Article › Academic › peer-review

11 Citations (Scopus)

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Abstract

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.

Original language	English
Pages (from-to)	1020-1029
Number of pages	10
Journal	European urology oncology
Volume	8
Issue number	4
DOIs	https://doi.org/10.1016/j.euo.2025.04.016
Publication status	Published - Aug 2025

Bibliographical note

Publisher Copyright:
Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.

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van Wilpe, S., Taha, T., Rothmann, E. C., Altshuler, E., Park, J., Ledet, E. M., Rothermundt, C., Bergman, A. M., Willemsen, A. E. C. A. B., Tsantoulis, P., Oldenburg, J., Bernard-Tessier, A., Fizazi, K., Robbrecht, D. G. J., Bruijnen, C. P., van der Hulle, T., Antonarakis, E. S., Omlin, A., Grönberg, H., ... Mehra, N. (2025). Efficacy of Anti-PD-(L)1 Immunotherapy in Patients with DNA Mismatch Repair-deficient Metastatic Castration-resistant Prostate Cancer. European urology oncology, 8(4), 1020-1029. https://doi.org/10.1016/j.euo.2025.04.016

@article{4b0bc854718d4523ab7214f24ff3bd03,

title = "Efficacy of Anti-PD-(L)1 Immunotherapy in Patients with DNA Mismatch Repair-deficient Metastatic Castration-resistant Prostate Cancer",

abstract = "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.",

author = "\{van Wilpe\}, Sandra and Tarek Taha and Rothmann, \{Emily C.\} and Ellery Altshuler and Joe Park and Ledet, \{Elisa M.\} and Christian Rothermundt and Bergman, \{Andre M.\} and Willemsen, \{Annelieke E.C.A.B.\} and Petros Tsantoulis and Jan Oldenburg and Alice Bernard-Tessier and Karim Fizazi and Robbrecht, \{Debbie G.J.\} and Bruijnen, \{Cheryl P.\} and \{van der Hulle\}, Tom and Antonarakis, \{Emmanuel S.\} and Aurelius Omlin and Henrik Gr{\"o}nberg and Armstrong, \{Andrew J.\} and Oliver Sartor and Sena, \{Laura A.\} and Himisha Beltran and \{de Bono\}, \{Johann S.\} and Niven Mehra",

year = "2025",

month = aug,

doi = "10.1016/j.euo.2025.04.016",

language = "English",

volume = "8",

pages = "1020--1029",

journal = "European urology oncology",

issn = "2588-9311",

publisher = "Elsevier",

number = "4",

}

van Wilpe, S, Taha, T, Rothmann, EC, Altshuler, E, Park, J, Ledet, EM, Rothermundt, C, Bergman, AM, Willemsen, AECAB, Tsantoulis, P, Oldenburg, J, Bernard-Tessier, A, Fizazi, K, Robbrecht, DGJ, Bruijnen, CP, van der Hulle, T, Antonarakis, ES, Omlin, A, Grönberg, H, Armstrong, AJ, Sartor, O, Sena, LA, Beltran, H, de Bono, JS & Mehra, N 2025, 'Efficacy of Anti-PD-(L)1 Immunotherapy in Patients with DNA Mismatch Repair-deficient Metastatic Castration-resistant Prostate Cancer', European urology oncology, vol. 8, no. 4, pp. 1020-1029. https://doi.org/10.1016/j.euo.2025.04.016

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

PY - 2025/8

Y1 - 2025/8

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.

UR - https://www.scopus.com/pages/publications/105016569968

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 -

Efficacy of Anti-PD-(L)1 Immunotherapy in Patients with DNA Mismatch Repair-deficient Metastatic Castration-resistant Prostate Cancer

Abstract

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