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.
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).
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.
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.
European urology oncology. 2025 Jul 11 [Epub ahead of print]
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
Medical Oncology Department, Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands. Electronic address: ., Institute of Cancer Research and Royal Marsden Hospital, London, UK., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Sidney Kimmel Comprehensive Cancer Centre, Johns Hopkins, Baltimore, MD, USA., Duke Cancer Institute Center for Prostate and Urologic Cancer, Duke University, Durham, NC, USA., Tulane Cancer Centre, Tulane University, New Orleans, LA, USA., Department of Medical Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland., Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands., Department of Internal Medicine, Tergooi Medical Centre, Hilversum, The Netherlands., Department of Oncology, Geneva University Hospitals, Geneva, Switzerland., Department of Oncology, Akershus University Hospital, Lørenskog, Norway., Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Saclay, Villejuif, France., Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands., Department of Medical Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands., Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands., Masonic Cancer Centre, University of Minnesota, Minneapolis, MN, USA., Onkozentrum Zurich, University of Zurich and Tumorzentrum Hirslanden Zurich, Zurich, Switzerland., Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden., Medical Oncology Department, Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands.
PubMed http://www.ncbi.nlm.nih.gov/pubmed/40651931