Apalutamide, Darolutamide and Enzalutamide for Nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC): A Critical Review

Simple Summary Apalutamide, darolutamide and enzalutamide are androgen-receptor signaling inhibitors proved to be useful in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). Although computed tomography and bone scans have been used to identify patients with nmCRPC in pivotal trials, currently, novel imaging techniques are widely used to stage patients, and they can detect metastases in many men with nmCRPC who are negative to conventional imaging. This review aims at discussing the role of apalutamide, darolutamide and enzalutamide in nmCRPC and the clinical implications of novel imaging techniques during treatment choice. Nonmetastatic castration-resistant prostate cancer (nmCRPC) represents a condition in which patients with prostate cancer show biochemical progression during treatment with androgen-deprivation therapy (ADT) without signs of radiographic progression according to conventional imaging. The SPARTAN, ARAMIS and PROSPER trials showed that apalutamide, darolutamide and enzalutamide, respectively, prolong metastasis-free survival (MFS) and overall survival (OS) of nmCRPC patients with a short PSA doubling time, and these antiandrogens have been recently introduced in clinical practice as a new standard of care. No direct comparison of these three agents has been conducted to support treatment choice. In addition, a significant proportion of nmCRPC on conventional imaging is classified as metastatic with new imaging modalities such as the prostate-specific membrane antigen positron emission tomography (PSMA-PET). Some experts posit that these "new metastatic" patients should be treated as mCRPC, resizing the impact of nmCRPC trials, whereas other authors suggest that they should be treated as nmCRPC patients, based on the design of pivotal trials. This review discusses the most convincing evidence regarding the use of novel antiandrogens in patients with nmCRPC and the implications of novel imaging techniques for treatment selection.