Introduction: The Challenge of Immunotherapy in Prostate Cancer
Metastatic castration-resistant prostate cancer (mCRPC) represents a significant clinical challenge, characterized by a complex genomic landscape and a historically ‘cold’ tumor immune microenvironment. While immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various solid tumors, their efficacy in unselected mCRPC patients has been modest. Large-scale Phase 3 trials, such as KEYNOTE-199 and KEYNOTE-921, failed to demonstrate a broad survival benefit for pembrolizumab in the general mCRPC population. However, these results masked the profound benefits observed in small, molecularly defined subsets of patients.
Currently, the FDA has granted tissue-agnostic approvals for ICIs in patients with microsatellite instability-high (MSI-H) or high tumor mutational burden (TMB-H, typically defined as ≥10 mutations per megabase). Despite these approvals, several clinical questions persist in the context of prostate cancer. Specifically, the independent utility of TMB-H in the absence of MSI-H remains debated, and the reliability of blood-based MSI (bMSI) testing as a surrogate for tissue-based testing in patients with limited biopsy material has not been fully elucidated. A recent study published in Clinical Cancer Research by Sayegh and colleagues provides critical evidence to address these gaps.
Study Design and Methodology
This investigation utilized the US-based deidentified Flatiron Health-Foundation Medicine prostate cancer Clinico-Genomic Database (FH-FMI CGDB). This robust dataset integrates longitudinal clinical data with comprehensive genomic profiling (CGP). The researchers identified 2,965 patients with mCRPC who underwent tissue-based assessment for MSI (tMSI) and TMB (tTMB) using an algorithm supporting an FDA-approved companion diagnostic (CDx).
The study focused on two primary cohorts. The first cohort consisted of patients treated with single-agent ICI therapy. Outcomes were analyzed based on tMSI and tTMB status, categorized into three groups: tMSI-H (regardless of TMB), tTMB ≥10 mut/Mb without tMSI-H, and a control group of tTMB < 10 without tMSI-H. The second cohort evaluated the clinical utility of blood-based MSI (bMSI) testing, comparing outcomes on ICI therapy for patients with bMSI-H versus those without, particularly focusing on the impact of circulating tumor DNA (ctDNA) fraction.
Primary endpoints included time to next treatment (TTNT) and overall survival (OS). To account for potential confounding factors, the researchers also performed intra-patient assessments, comparing TTNT on ICI therapy to TTNT on a prior taxane-based chemotherapy regimen.
Key Findings: Tissue-Based Biomarkers
Among the nearly 3,000 patients screened, the prevalence of tMSI-H was 3.2%. Notably, tMSI-H was almost always comorbid with high tumor mutational burden; the majority of tMSI-H patients also exhibited tTMB ≥10 mut/Mb. However, a distinct subset of patients (approximately 1.5% of the total cohort) was identified as having tTMB ≥10 without being MSI-H.
In the 84 patients treated with ICI monotherapy, the results were striking. Both tMSI-H and tTMB-H (non-MSI-H) status were associated with significantly superior outcomes compared to the biomarker-negative group:
tMSI-H Outcomes
Patients with tMSI-H (any TMB) demonstrated a dramatic reduction in the risk of treatment progression and death. The Hazard Ratio (HR) for TTNT was 0.18 (95% CI: 0.09-0.37), and the HR for OS was 0.32 (95% CI: 0.15-0.66). These data reinforce the established role of MSI-H as a primary predictor of ICI benefit.
tTMB ≥10 (Non-MSI-H) Outcomes
Crucially, patients who were tTMB ≥10 but lacked MSI-H also derived significant benefit. For this group, the HR for TTNT was 0.18 (95% CI: 0.04-0.48) and the HR for OS was 0.20 (95% CI: 0.05-0.77). This finding is particularly important as it suggests that TMB-H is not merely a proxy for MSI-H in prostate cancer but serves as an independent predictor of response, potentially identifying a broader range of patients who can benefit from immunotherapy.
The Role of Liquid Biopsy: Blood-Based MSI
Given that metastatic prostate cancer often spreads to the bone, obtaining adequate tissue for CGP can be challenging. The study addressed this by evaluating blood-based MSI (bMSI). The detection of bMSI-H was found to be a reliable predictor of ICI success, provided there was sufficient circulating tumor DNA. When the tumor fraction in the blood was ≥1%, bMSI-H was associated with a more favorable TTNT (HR: 0.34, 95% CI: 0.14-0.83) and OS (HR: 0.21, 95% CI: 0.06-0.75). This provides clinicians with a viable alternative when tissue is unavailable or insufficient, emphasizing the importance of the tumor fraction in liquid biopsy interpretation.
Comparative Efficacy: ICI vs. Taxanes
To further validate these biomarkers as predictive rather than merely prognostic, the researchers conducted an intra-patient analysis. In patients with tTMB ≥10, the duration of benefit (TTNT) was significantly longer with ICI therapy compared to their prior taxane-based therapy. This suggest that the biomarkers specifically identify sensitivity to immune checkpoint blockade rather than just identifying a subset of patients who have an inherently better prognosis regardless of the treatment used.
Expert Commentary and Clinical Implications
The findings from this study have immediate implications for the management of mCRPC. First, they validate the use of TMB ≥10 as a meaningful threshold for ICI selection in prostate cancer, even in the absence of MSI-H. While the prevalence of these markers is relatively low (roughly 5% combined), the magnitude of benefit is substantial, often leading to durable responses that are rarely seen with standard chemotherapy or androgen receptor signaling inhibitors (ARSIs).
From a mechanistic perspective, the efficacy of ICIs in TMB-H and MSI-H tumors is driven by the high load of neoantigens. These mutations result in the production of ‘non-self’ proteins that the immune system can recognize once the inhibitory signals (PD-1/PD-L1) are blocked. The study’s confirmation that both markers independently contribute to this predictive power supports a more comprehensive approach to genomic screening.
However, limitations must be noted. This was a retrospective analysis of a clinico-genomic database. While the sample size for screening was large, the number of patients actually treated with ICI monotherapy was relatively small (n=84), reflecting the current standard-of-care landscape where ICIs are reserved for later lines of therapy or specific biomarker-positive cases. Additionally, the success of liquid biopsy is heavily dependent on the tumor fraction, meaning a ‘negative’ bMSI result in a patient with low circulating tumor DNA does not necessarily rule out MSI-H status in the tissue.
Conclusion
The study by Sayegh et al. provides robust real-world evidence supporting the additive clinical utility of tTMB and tMSI in predicting the effectiveness of ICI monotherapy in mCRPC. By demonstrating that TMB-H (non-MSI-H) patients derive similar levels of benefit to MSI-H patients, the study expands the potential population that can be targeted with precision immunotherapy. Furthermore, the validation of bMSI-H in patients with adequate tumor fraction offers a critical alternative for molecular stratification. For clinicians, the message is clear: early and comprehensive genomic profiling—whether through tissue or blood—is essential to ensure that mCRPC patients are not deprived of potentially life-extending 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. Marcus L, Lemery SJ, Keegan P, Pazdur R. FDA Approval Summary: Pembrolizumab for the Treatment of Microsatellite Instability-High Solid Tumors. Clin Cancer Res. 2019;25(13):3753-3758.
3. de Bono JS, Goh JC, Ojamaa K, et al. KEYNOTE-921: Phase III study of pembrolizumab plus docetaxel for metastatic castration-resistant prostate cancer. J Clin Oncol. 2023;41(16_suppl):5001.