Immune Checkpoint Blockade for Prostate Cancer: Niche Role or Next Breakthrough?

Abstract

A number of trials have evaluated the use of single-agent immune checkpoint inhibitors for the treatment of metastatic castration-resistant prostate cancer (mCRPC). The benefit appears to be limited to a small subset of patients, such as those with tumors with microsatellite instability, highlighting the importance of biomarkers to identify which patients may be more likely to respond. Given the lack of efficacy for most patients with mCRPC, our understanding of the mechanisms of primary resistance to checkpoint inhibitors and of the tumor immune microenvironment in prostate cancer is critical. Knowledge gained in these key areas will allow for the identification of novel combination therapies that will circumvent resistance mechanisms and should be tested in clinical trials. Improving our understanding of the effects of androgen deprivation therapy on immune cells and of the most favorable disease setting (e.g., biochemically recurrent vs. castration-resistant prostate cancer) may aid in the optimal use of checkpoint inhibitors in combination with other agents. If successful, this may move immune checkpoint inhibitors into the treatment armamentarium of prostate cancer management.

225Actinium-labeled prostate-specific membrane antigen targeting peptide induces complete response in a metastatic prostate cancer patient

“…11,12 TMB is an emerging, independent biomarker of outcomes with immunotherapy in multiple tumor types, including prostate cancer. 13 However, metastatic prostate cancer generally has a low TMB (median, 2.9 mutations/megabyte), and only 3.0%-8.3% of advanced prostate cancer tumors have a high TMB. 14,15 In the CheckMate 650 trial, treatment with ICIs (ipilimumab and nivolumab) resulted in an objective response rate of Fig.…”

“…TMB is an emerging, independent biomarker of outcomes with immunotherapy in multiple tumor types, including prostate cancer. 13 However, metastatic prostate cancer generally has a low TMB (median, 2.9 mutations/megabyte), and only 3.0%–8.3% of advanced prostate cancer tumors have a high TMB. 14 , 15 In the CheckMate 650 trial, treatment with ICIs (ipilimumab and nivolumab) resulted in an objective response rate of 56.3% in patients with a TMB above the median (74.5 mutations/patient); patients with a TMB above the median also had longer radiographic progression-free survival when compared with those with a TMB below the median (7.4 months [95% CI, 6.5 months to not estimated] vs. 2.4 months [95% CI, 1.8–3.9 months], p < 0.0001).…”

Metastatic Spread in Prostate Cancer Patients Influencing Radiotherapy Response

“…Jiao et al. hypothesize that this mechanism is the key factor that explains the lack of clinical efficiency of immunotherapies in metastatic CRPC patients and indicates the potential of immune checkpoint therapy in combination with TGF-β inhibitors ( 285 , 286 ). A recently published study demonstrated that the immunosuppressive microenvironment within PCa bone metastasis can be targeted via the CCL20-CCR6 axis.…”

Evolving Role of Immunotherapy in Metastatic Castration Refractory Prostate Cancer

“…Furthermore, NCT04116775 is evaluating fecal microbiota transplant with pembrolizumab in patients with mCRPC. Other agents that are being evaluated in combination with PD-1-directed therapies in the mCRPC setting include ipatasertib (AKT inhibitor; NCT03673787), isatuximab (anti-CD38 antibody; NCT03367819), naptumomab (5T4-targeted immunotoxin; NCT03983954), GB1275 (CD11b agonist; NCT04060342), utomilumab (4-1BB antibody; NCT03217747), and PF-4518600 (OX40 receptor agonist; NCT03217747) [104].…”