Combination therapy in metastatic hormone-sensitive prostate cancer: is three a crowd?

The mainstay of treatment for metastatic prostate cancer is androgen deprivation therapy (ADT). Outcomes with ADT are variable but control of hormone-sensitive prostate cancer (HSPC) can often be achieved for many years. Death from prostate cancer is usually due to the development of escape variants able to survive and proliferate in the setting of castrate levels of serum androgens (metastatic castration-resistant prostate cancer, mCRPC). Several agents can improve survival for patients with mCRPC, including chemotherapy, agents to reduce androgen receptor signalling, the radioisotope radium-223 dichloride, and cellular immunotherapy with sipuleucel-T. Some of these agents have been moved earlier in the disease course and have shown to improve survival in metastatic HSPC also, often to a much greater degree than when the same agents are used in mCRPC. Specifically, survival of metastatic HSPC can be improved with the addition to ADT of any one of docetaxel, abiraterone acetate/prednisone combination, apalutamide, enzalutamide, or darolutamide in combination with docetaxel. Factors affecting outcomes include the volume or burden of disease, timing of metastases relative to the original diagnosis, and patient factors determining the appropriateness of therapy. Unfortunately, uptake of this information by the clinical community remains suboptimal, with many men potentially suitable for combination therapy still receiving only ADT. Some trials have examined the effects of 'triplet' therapies although few were designed specifically to address this question. The best evidence to date suggests that triplet therapy with ADT + abiraterone + docetaxel or ADT + darolutamide + docetaxel, can improve overall survival in metastatic HSPC. Clear opportunities exist to improve survival outcomes for men with metastatic HSPC but need to be balanced against cost, accessibility, toxicity, and patient-specific factors.