Prostate cancer has historically been considered immunologically unresponsive due to lower tumor mutation burden when compared with other cancers. However, research over the years has led to the establishment of a role for immunotherapy in CRPC, with the following 2 related US Food and Drug Administration (FDA) approvals: autologous cellular immunotherapy with sipuleucel-T (Sip-T) and immune checkpoint blockade with pembrolizumab for the treatment of microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) solid tumors.

Sip-T is indicated for the treatment of asymptomatic or minimally symptomatic metastatic CRPC. It is 1 of several FDA-approved therapies in this space that can prolong overall survival (OS). However, with Sip-T there is a disconnect between OS and progression-free survival (PFS). It does not appear to impact PFS, and I believe that this has limited its acceptance by clinicians. Different patient populations may have different responses to Sip-T; an exploratory analysis from PROCEED found that, at a median follow-up of 46.6 months, among baseline prostate-specific antigen–matched men receiving Sip-T, the median OS was longer in African Americans than in Caucasians. This is quite interesting because similar findings have been reported in studies of other treatments (ie, that African American patients with CRPC have a better survival than Caucasian patients when treated with chemotherapy and adjusted for prognostic factors). The underlying reasons and/or mechanisms are unknown.

As relates to immune checkpoint inhibition, a recent case series from Memorial Sloan Kettering Cancer Center examined the prevalence of microsatellite instability in prostate cancer and its association with response to immune checkpoint blockade. Findings suggested that, although the MSI-H/dMMR molecular phenotype is uncommon, it may be therapeutically meaningful. Further, combination strategies are being actively explored to determine whether responses to immunotherapy can be improved upon. For instance, combinations of 2 immune checkpoint inhibitors or an immune checkpoint inhibitor plus a second-generation androgen receptor antagonist are under evaluation.

Monotherapy with immune checkpoint inhibitors has shown limited activity in prostate cancer, but the phase 2 CheckMate 650 study reported that nivolumab plus ipilimumab had antitumor activity in patients with metastatic CRPC. Further, there is interest in potentially enhancing the response to immune checkpoint inhibitors by promoting an immune-permissive microenvironment with agents such as cabozantinib, a tyrosine kinase inhibitor. In COSMIC-021, a phase 1B study of metastatic CRPC, an objective response rate of 32% was seen with atezolizumab when combined with cabozantinib. These findings were encouraging because, when used as monotherapy, each of these agents had an objective response rate of 5% or less. Another approach under evaluation is the combination of an immune checkpoint inhibitor with a radioactive isotope (eg, pembrolizumab plus radium-223). So, a number of strategies are being investigated in an attempt to improve responses to immunotherapy in patients with advanced disease.