Immunotherapy and Immunotherapy Combinations in Metastatic Castration-Resistant Prostate Cancer

SIMPLE SUMMARY: Immunotherapy has changed the treatment paradigm of numerous malignancies such as non-small cell lung cancer and melanoma. To date, there has been only modest demonstrable efficacy of immunotherapy for prostate cancer. This lack of efficacy is likely due to the immunosuppressive tumor microenvironment. When we consider the fact that metastatic castrate-resistant state is the most lethal form of prostate cancer, there is an unmet need to increase the efficacy of immune therapies for this disease. The treatment paradigm has now shifted towards combinatorial regimens to enhance the anti-tumor immune response. These combinations with immunomodulatory agents in ongoing clinical trials include conventional agents such as chemotherapy and numerous novel agents. This review summarizes the clinical trials recruiting patients with metastatic castrate-resistant prostate cancer utilizing immunotherapeutic approaches. ABSTRACT: Although most prostate cancers are localized, and the majority are curable, recurrences occur in approximately 35% of men. Among patients with prostate-specific antigen (PSA) recurrence and PSA doubling time (PSADT) less than 15 months after radical prostatectomy, prostate cancer accounted for approximately 90% of the deaths by 15 years after recurrence. An immunosuppressive tumor microenvironment (TME) and impaired cellular immunity are likely largely responsible for the limited utility of checkpoint inhibitors (CPIs) in advanced prostate cancer compared with other tumor types. Thus, for immunologically “cold” malignancies such as prostate cancer, clinical trial development has pivoted towards novel approaches to enhance immune responses. Numerous clinical trials are currently evaluating combination immunomodulatory strategies incorporating vaccine-based therapies, checkpoint inhibitors, and chimeric antigen receptor (CAR) T cells. Other trials evaluate the efficacy and safety of these immunomodulatory agents’ combinations with standard approaches such as androgen deprivation therapy (ADT), taxane-based chemotherapy, radiotherapy, and targeted therapies such as tyrosine kinase inhibitors (TKI) and poly ADP ribose polymerase (PARP) inhibitors. Here, we will review promising immunotherapies in development and ongoing trials for metastatic castration-resistant prostate cancer (mCRPC). These novel trials will build on past experiences and promise to usher a new era to treat patients with mCRPC.