Tumor mutational burden to predict immunotherapy benefit in prostate cancer
Metastatic castration-resistant prostate cancer remains a serious and often fatal disease, even though systemic treatment options have improved. Patients may be treated with androgen receptor-targeted therapies, taxane-based chemotherapy, PARP inhibitors, or radiation therapy, all of which have shown to extend patient survival. However, the use of immunotherapy, which has been shown to improve survival in many other tumor types, has faced challenges in metastatic castration-resistant prostate cancer (mCRPC). Immune checkpoint inhibitors, such as pembrolizumab and dostarlimab, help a patient’s immune system recognize and attack cancer cells. These therapies are highly effective for cancers with specific molecular features, particularly high tumor mutational burden (TMB) and high microsatellite instability (MSI-H). TMB is defined as the number of mutations per megabase. Tumors with many mutations are more likely to produce abnormal proteins and neoantigens that can be recognized by the immune system. Similarly, MSI-H is caused by defects in DNA repair pathways, which almost always result in high TMB. It has been shown that patients with mCRPC who have high TMB or MSI-H derive greater benefit from immune checkpoint inhibitor therapy, while patients who have tumors without these features often respond better to taxane-based chemotherapy. While most MSI-H prostate cancers are TMB high, there are a small number of tumors with high TMB that are not MSI-H. Due to the limited size of prior data sets, it has not previously been feasible to evaluate this rare subpopulation. Therefore, the authors conducted a large retrospective study in which they used the hybrid capture-based FoundationOne CDx genomic profiling platform, which assesses both MSI and TMB, to characterize tumors and examine outcomes in patients with mCRPC. Clinical outcomes were measured using overall survival and time to next treatment, with the latter defined as the time from starting a therapy until the next line of treatment or death. Among 2,965 patients analyzed, 95 (3.2 percent) were MSI-H, 48 (1.7 percent) were TMB high without MSI-H, and 2,822 (95.2 percent) were microsatellite stable with low TMB. Importantly, the group of patients with TMB high without MSI-H tumors had clinical outcomes similar to those with MSI-H disease when treated with immune checkpoint inhibitors. In contrast, patients with low TMB and microsatellite-stable tumors had better outcomes with taxane-based chemotherapy. The authors also examined a subgroup of 50 patients who had taxane-based chemotherapy followed by subsequent immune checkpoint inhibitor treatment, a subgroup analysis that minimized confounding variables by following the same individual patients longitudinally. It was found that those with high TMB had longer benefit from immune checkpoint inhibitors than from the taxane-based chemotherapy, whereas those with low TMB benefitted more from taxane-based chemotherapy. Overall, the findings from this study suggest that high TMB, even without MSI-H status, identifies a biologically meaningful subgroup of mCRPC patients who may benefit from immune checkpoint inhibitors. This study also highlights the growing importance of comprehensive genomic profiling and determining MSI and TMB status for the purpose of guiding treatment decisions.
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. doi.org/10.1158/1078-0432.CCR-25-2750
Correspondence: Dr. Tian Zhang at [email protected] or Dr. Neeraj Agarwal at [email protected]