Introduction: The Challenge of the ‘Cold’ Prostate Tumor
Metastatic castration-resistant prostate cancer (mCRPC) has historically been characterized as an immunologically ‘cold’ tumor. Unlike melanoma or non-small cell lung cancer, mCRPC typically exhibits a low mutational burden and a suppressive tumor microenvironment, leading to disappointing results for immune checkpoint inhibitors (ICIs) in unselected patient populations. Despite this, the FDA has granted tissue-agnostic approvals for ICIs like pembrolizumab for tumors exhibiting microsatellite instability-high (MSI-H) or high tumor mutational burden (TMB-H, defined as ≥10 mutations per megabase). However, the specific clinical utility of these biomarkers within the prostate cancer landscape—particularly the additive value of TMB in the absence of MSI-H—has remained an area of active investigation. A new study published in Clinical Cancer Research provides critical evidence on how these biomarkers should guide clinical decision-making.
Study Design and Methodology
The researchers utilized the US-based deidentified Flatiron Health-Foundation Medicine prostate cancer Clinico-Genomic Database (FH-FMI CGDB). This robust dataset allowed for the analysis of 2,965 patients with mCRPC who underwent comprehensive genomic profiling. The study specifically focused on patients with tissue-assessed MSI (tMSI) and TMB (tTMB) status determined by an FDA-approved companion diagnostic algorithm. The primary objectives were to evaluate the effectiveness of single-agent ICI therapy based on biomarker status and to assess the utility of blood-based MSI (bMSI) testing. Outcomes were measured using Time to Next Treatment (TTNT) and Overall Survival (OS). Additionally, an intra-patient assessment compared outcomes of ICI therapy versus prior taxane-based chemotherapy in patients with tTMB ≥10.
Key Findings: The Prevalence and Predictive Power of Biomarkers
Among the nearly 3,000 patients analyzed, tMSI-H was identified in 3.2% of the cohort. Notably, tMSI-H was almost always comorbid with high TMB; specifically, patients with tMSI-H nearly always exceeded the tTMB ≥10 mut/Mb threshold. However, a distinct subset of patients exhibited TMB-H without MSI-H, representing 4.7% of the total population. These findings emphasize that while MSI-H and TMB-H overlap, they are not identical clinical entities in mCRPC.
Clinical Outcomes by Tissue Biomarker Status
In 84 patients treated with ICI monotherapy, the presence of these biomarkers was strongly associated with improved clinical outcomes:
- tMSI-H Group: Patients with tMSI-H (regardless of TMB level) showed a significantly more favorable TTNT (Hazard Ratio [HR]: 0.18; 95% CI: 0.09-0.37) and OS (HR: 0.32; 95% CI: 0.15-0.66) compared to the biomarker-negative group (tTMB <10 and non-MSI-H).
- tTMB-H (Non-MSI-H) Group: Crucially, patients who were tTMB ≥10 but not MSI-H also derived significant benefit from ICIs. This group demonstrated a TTNT HR of 0.18 (95% CI: 0.04-0.48) and an OS HR of 0.20 (95% CI: 0.05-0.77).
These data suggest that TMB-H status alone, even in the absence of MSI-H, is a potent predictor of ICI response in mCRPC, a finding that expands the pool of patients who may benefit from immunotherapy beyond the traditional MSI-H definition.
Intra-patient Comparisons and Liquid Biopsy Utility
To further validate the benefit of ICIs, the study performed an intra-patient analysis. In patients with tTMB ≥10, TTNT was more favorable when they received a subsequent ICI compared to their previous taxane-based therapy. This provides a direct clinical rationale for prioritizing immunotherapy in this biomarker-selected subset over traditional cytotoxic options.
Furthermore, the study addressed the common clinical hurdle of insufficient tissue for biopsy. Assessing blood-based MSI (bMSI), the researchers found that bMSI-H was associated with favorable TTNT (HR: 0.34) and OS (HR: 0.21) on ICI therapy, provided the tumor fraction in the blood was ≥1%. This highlights the potential of liquid biopsies as a reliable surrogate when tissue is unavailable or difficult to obtain.
Expert Commentary and Clinical Implications
The results of this study are transformative for the management of advanced prostate cancer. For years, the ‘cold’ nature of prostate cancer led to a degree of nihilism regarding immunotherapy. However, these data confirm that for the ~5-8% of patients with MSI-H or TMB-H status, ICI monotherapy is not just an option, but perhaps the most effective strategy. The finding that TMB-H without MSI-H still confers a significant survival advantage is particularly important, as it reinforces the need for comprehensive genomic profiling rather than just MSI testing.
From a methodological standpoint, the use of the FH-FMI CGDB provides a high level of real-world evidence that complements clinical trial data. Limitations of the study include its retrospective nature and the relatively small sample size of the ICI-treated cohort (n=84), which is a reflection of the rarity of these biomarkers in the general mCRPC population. Future research should focus on whether combining ICIs with other agents (like PARP inhibitors or radiotherapy) can further enhance responses in these subgroups or even sensitize biomarker-negative patients.
Conclusion
This large-scale clinico-genomic analysis provides robust evidence that tTMB ≥10 mut/Mb and tMSI-H are independent and additive predictors of ICI effectiveness in mCRPC. The study successfully validates the use of pembrolizumab and other ICIs in these specific genomic subsets and introduces blood-based MSI testing as a viable clinical tool. For clinicians, the takeaway is clear: comprehensive genomic profiling—whether through tissue or liquid biopsy—is essential in the mCRPC setting to identify the small but significant percentage of patients who can achieve durable responses with immunotherapy.
References
1. Sayegh N, Graf RP, Swami U, et al. Additive Clinical Utility of Microsatellite Instability and Tumor Mutational Burden to Predict Immune Checkpoint Inhibitor Effectiveness in Metastatic Castration-Resistant Prostate Cancer. Clin Cancer Res. 2025 Dec 4. doi: 10.1158/1078-0432.CCR-25-2750. PMID: 41342879.
2. Abida W, Cheng ML, Armenia J, et al. Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA Oncol. 2019;5(4):471-478.
3. Marcus L, Lemery SJ, Keegan P, Pazdur R. FDA Approval Summary: Pembrolizumab for the Treatment of Tumor Mutational Burden-High Solid Tumors. Clin Cancer Res. 2021;27(17):4685-4689.
