The recent changes in the treatment of prostate cancer have been quite dramatic. This evolution really began in 2015 with the success of upfront androgen deprivation therapy (ADT) plus docetaxel in patients with high-volume, metastatic hormone-sensitive prostate cancer (mHSPC). Another major advance occurred in this setting in 2017 with ADT plus abiraterone. Then, at the 2019 American Society of Clinical Oncology Annual Meeting, we had 2 more breakthrough studies in mHSPC reporting on the use of ADT plus enzalutamide and ADT plus apalutamide, both of which were strongly positive for overall survival benefits and a number of secondary end points. We also learned that the triplet regimen of enzalutamide plus ADT plus docetaxel was not really any better than ADT plus docetaxel alone. 

We have been working to change the natural history of castration-resistant prostate cancer (CRPC) over the last 10 to 15 years with treatments such as abiraterone, enzalutamide, cabazitaxel, docetaxel, radium-223, and sipuleucel-T. One of the most recent alterations to the treatment landscape involves assessing CRPC based on the presence or absence of metastatic disease on conventional imaging. In this context, castration resistance means that the prostate-specific antigen (PSA) is rising despite a castration level of testosterone. 

A series of trials in patients with nonmetastatic CRPC (nmCRPC) examining enzalutamide, apalutamide, and darolutamide—all 3 of which now have US Food and Drug Administration approval—have shown that the time to metastases was substantially prolonged within the group of patients with nmCRPC and a PSA doubling time of 10 months or less. I think that all of these trials will show survival benefits with subsequent additional follow-up. Shorter time to metastasis is a surrogate for a number of poor outcomes, including decreased survival. With the approval of these 3 agents in the nonmetastatic space, the question now becomes: When should clinicians use them? I envision that they will be used in patients with more rapid PSA progression. Each agent is fairly well tolerated; apalutamide has some reports of rash and hypothyroidism and enzalutamide has some reports of fatigue. The darolutamide trials look quite good in terms of side effects, but we know that, with clinical experience, there may be adverse events that are not appreciated initially. 

In summary, we are in the midst of a paradigm shift in prostate cancer treatment, and these new studies of combination therapies have changed the way we view and approach advanced disease, including nmCRPC.