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

While metastatic castration-resistant prostate cancer (mCRPC) is generally resistant to immune checkpoint blockade, a small subset of patients—estimated at 5%—exhibit deficient mismatch repair (dMMR), leading to a hypermutated, microsatellite instability-high (MSI-H) phenotype amenable to immunotherapy. Until now, clinical evidence on the efficacy of immune checkpoint blockade in this molecular subgroup has been limited, and access to these agents is not universally available across healthcare systems.

Study Approach

This international, multicentre study investigated the efficacy of anti-PD-(L)1 monotherapy in patients with dMMR mCRPC. Clinical data of 93 patients with dMMR mCRPC were retrospectively collected from hospitals in seven different countries. dMMR was defined as MMR protein loss on immunohistochemistry, a deleterious alteration in an MMR gene and/or MSI-H status. The primary endpoint was progression-free survival (PFS).

Key Findings

Anti-PD-(L)1 monotherapy is a highly effective treatment option for patients with dMMR mCRPC with an objective response rate of 46%, a median PFS of 7.7 months (95% CI 5.3-12.4) and a median overall survival of 27.0 months (95% CI 17.7-43.5).
Progression-free survival reaches a plateau at 2 to 3 years, with 26% of patients still progression-free after 3 years.
Patients with consensus dMMR according to two or more tests derive more benefit from immune checkpoint blockade than those with only one positive test, indicating that patients should be preferably selected by a combination of tests. If access to next-generation sequencing is limited, immunohistochemical assessment of MMR proteins alone might be a reasonable alternative.

Clinical Implications

This study provides compelling evidence that anti-PD-(L)1 therapy offers substantial clinical benefit to patients with dMMR mCRPC. Given these results, its reconsideration as a reimbursable treatment option is warranted, particularly in healthcare systems where access to immune checkpoint inhibitors remains limited. Notably, even in jurisdictions where reimbursement is currently approved, the use of immune checkpoint blockade is typically restricted to patients who have exhausted other treatment options. In light of the observed efficacy, re-evaluating current treatment sequencing within the mCRPC setting may be justified. Moreover, our findings underscore the need for collaborative international efforts to investigate immune checkpoint blockade in earlier disease settings, including metastatic castration-sensitive prostate cancer.

Written by: Sandra van Wilpe,¹ Tarek Taha,² Emily C Rothmann,³ Ellery Altshuler,⁴ Joe Park,⁵ Elisa M Ledet,⁶ Christian Rothermundt,⁷ Andre M Bergman,⁸ Annelieke E C A B Willemsen,⁹ Petros Tsantoulis,¹⁰ Jan Oldenburg,¹¹ Alice Bernard-Tessier,¹² Karim Fizazi,¹² Debbie G J Robbrecht,¹³ Cheryl P Bruijnen,¹⁴ Tom van der Hulle,¹⁵ Emmanuel S Antonarakis,¹⁶ Aurelius Omlin,¹⁷ Henrik Grönberg,¹⁸ Andrew J Armstrong,⁵ Oliver Sartor,⁶ Laura A Sena,⁴ Himisha Beltran,³ Johann S de Bono,² Niven Mehra¹

Medical Oncology Department, Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands.
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.

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