A Multi-Disciplinary Review of the Evidence Supporting Metastasis-Free Survival (MFS) and the Benefit of Delaying Metastasis in High-Risk Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC)

Abstract

Until recently, men diagnosed with high-risk non-metastatic castrate-resistant prostate cancer (nmCRPC) were faced with the prospect of a relatively short reprieve from symptomatic progression before the onset of metastatic disease. Crossing this red line represents a turning point in the disease, characterised by debilitating pain, greater functional and emotional impairment, a need for additional treatments, and, eventually, death. Delaying time to metastatic progression has the potential to limit symptomatic progression, reduce morbidity and mortality, and maintain quality of life in nmCRPC, and efforts have been made to establish the validity of metastatic-free survival (MFS) as a valid and meaningful clinical endpoint in this setting. The approval in Europe of apalutamide and enzalutamide based on the Phase III SPARTAN (NCT01946204) and PROSPER (NCT02003924) trials, respectively, with MFS as a primary endpoint (defined as time from randomisation to first radiographic detection of distant metastases, or death) sets a new precedent for future trials in nmCRPC. Although median overall survival (OS) has not yet been reached in either trial, meta-analyses of the two studies suggest a significant improvement in OS alongside a confirmed improvement in MFS for novel anti-androgens versus placebo. A third drug, darolutamide, has also been submitted for regulatory approval to treat nmCRPC. This review aims to summarise the evidence supporting the use of MFS as a clinical endpoint and the benefit of delaying metastasis in men with high-risk nmCRPC, and to discuss the influence of next-generation imaging on prostate cancer staging.