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Mismatch Repair Deficiency, Microsatellite Instability and Hypermutation in Prostate Cancer…a Good Match for Immunotherapy

Mismatch repair deficiency (dMMR), microsatellite instability (MSI-H), and high tumor mutational burden (TMB-H) have emerged as clinically important biomarkers in prostate cancer with direct therapeutic implications. Although they occur in only a small fraction of cases, these alterations define a subset of tumors with increased immunogenicity and enhanced sensitivity to immune checkpoint blockade. In metastatic castration-resistant prostate cancer (mCRPC), where immunotherapy typically has limited benefit, identification of MSI-H/dMMR or TMB-H provides access to pembrolizumab under FDA tissue-agnostic approvals.1,2

Mismatch repair deficiency results from inactivation of DNA repair proteins such as MLH1, MSH2, MSH6, or PMS2. Loss of mismatch repair function leads to insertion-deletion mutations at short tandem repeats (microsatellite instability), increasing tumor mutational load and neoantigen production: thereby, sensitizing tumors to PD-1 blockade.3 Tumor mutational burden, measured as the number of somatic mutations per megabase (mut/Mb), is another proxy for neoantigen burden; the FDA’s tissue-agnostic TMB-H threshold (≥10 mut/Mb) was derived from pembrolizumab efficacy data across multiple tumor types.2,4

The prevalence of MSI-H/dMMR in prostate cancer is low but clinically meaningful. In a large institutional cohort analyzed with targeted sequencing, approximately 3.1% of evaluable tumors were MSI-H/dMMR, and roughly 22% of those cases carried pathogenic germline Lynch-syndrome–associated variants, highlighting hereditary implications.5 A larger MSK-IMPACT analysis across thousands of tumors found 2.8% were MSI-H/dMMR and 1.5% were TMB-H but microsatellite stable (MSS); this also showed that MSI-H/dMMR tumors tended to present with higher grade and de novo metastatic disease.3 While overall dMMR is uncommon, it is enriched in very high-grade disease: focused primary-tumor studies have shown MMR (e.g., MSH2) protein loss is most frequent among Gleason pattern 5 tumors compared with lower-grade tumors.6

TMB-H without concurrent MSI-H is rare in prostate cancer (approximately 1–2% in large genomic series) and often overlaps with MSI-H when present.3 Because MSI-H/dMMR tumors typically have higher indel burden, neoantigen load, and TMB than MSS tumors, MSI-H/dMMR status has emerged as a more consistent predictor of checkpoint-inhibitor sensitivity in this disease.3

Although these biomarker-defined subgroups are small, clinical responses to PD-1 blockade can be meaningful and durable. In the MSK cohort, 15 of 23 (65%) MSI-H/dMMR patients treated with immune checkpoint blockade achieved a ≥50% decline in PSA (PSA₅₀), while 9 of 20 (45%) had RECIST partial or complete responses; by contrast, among TMB-H/MSS patients the PSA₅₀ rate was 3 of 6 (50%) and no RECIST responses were observed.3 In the multi-institutional JAMA Oncology case series, 6 of 11 (54.5%) MSI-H/dMMR mCRPC patients receiving anti-PD-1/PD-L1 therapy achieved a >50% PSA decline, and 5 of those responders (5 of 11 total; 45.5%) remained on therapy at last follow-up (up to ~89 weeks), indicating durability.5 In a circulating-tumor-DNA–identified series, 4 of 9 (44%) patients achieved PSA₅₀, and three patients had >99% PSA declines; median time on pembrolizumab in that cohort was approximately 9.9 months.7 Taken together, these datasets show consistent, sometimes deep and durable, responses in the MSI-H/dMMR subset and more variable benefit in TMB-H/MSS disease.3,5,7

Regulatory guidance conforms with these observations: in May 2017, the FDA granted the first tissue-agnostic approval to pembrolizumab for unresectable or metastatic MSI-H/dMMR solid tumors, and in June 2020, the agency granted a second tissue-agnostic accelerated approval for pembrolizumab in TMB-H (≥10 mut/Mb) solid tumors.1,2 KEYNOTE-158 performed a prospective biomarker study that supported the link between higher tissue TMB and pembrolizumab activity across multiple tumor types, which informed the TMB-H indication.4

In summary, MSI-H/dMMR and TMB-H define a small but therapeutically important subset of prostate cancers. MSI-H/dMMR in particular predicts a high likelihood of meaningful and sometimes durable responses to PD-1 blockade, whereas TMB-H without MSI-H is rarer and confers more variable benefit. Detection of MSI-H/dMMR should also prompt consideration of germline evaluation for Lynch syndrome and genetic counseling. These biomarkers, therefore, enable precision immunotherapy in a disease that is otherwise relatively resistant to checkpoint blockade. Ongoing clinical trials exploring immunotherapy in MMRd/MSI-H and high-TMB prostate cancer are described below:

Ongoing clinical trials for prostate cancer patients with MSI-H/dMMR or TMB-H tumors:

  • CHOMP – Pembrolizumab for dMMR or CDK12 biallelic inactivation with mCRPC (NCT04104893)
  • Nivolumab for dMMR, MSI-H, TMB-H biochemically-recurrent prostate cancer (NCT04019964)
  • PERSEUS1 – Pembrolizumab for dMMR, MSI-H, or TMB-H with mCRPC (NCT03506997)
  • Impact of DNA repair alterations, including dMMR on sensitivity to radium-223 for patients with bone mCRPC (NCT04489719)
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. U.S. Food and Drug Administration. FDA grants accelerated approval to pembrolizumab for first tissue/site-agnostic indication (MSI-H/dMMR solid tumors). May 23, 2017.
  2. U.S. Food and Drug Administration. FDA approves pembrolizumab for adults and children with TMB-H solid tumors (≥10 mut/Mb). June 16, 2020.
  3. Lenis AT, Ravichandran V, Brown S, et al. Microsatellite instability, tumor mutational burden, and response to immune checkpoint blockade in patients with prostate cancer. Clin Cancer Res. 2024;30(17):3894–3903.
  4. Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab (KEYNOTE-158). Lancet Oncol. 2020;21(10):1353–1365.
  5. Abida W, Cheng ML, Armenia J, et al. Analysis of the prevalence and clinical outcomes of mismatch repair deficiency in metastatic prostate cancer. JAMA Oncol. 2019;5(4):471–478.
  6. Guedes LB, Antonarakis ES, Schweizer MT, et al. MSH2 loss in primary prostate cancer. Clin Cancer Res. 2017;23(22):6863–6874.
  7. Barata P, Agarwal N, Nussenzveig R, et al. Clinical activity of pembrolizumab in metastatic prostate cancer with microsatellite instability high (MSI-H) detected by circulating tumor DNA. J Immunother Cancer. 2020;8(2):e001065.