Update on the Management of Non-Metastatic Castration-Resistant Prostate Cancer

Abstract

Background: Non-metastatic Castration Resistant Prostate Cancer (nmCRPC) is a heterogenous disease state in which the epidemiology is not completely known. Development of more sensitive modalities for detection of metastasis as well as the emerging data on new generation Androgen Receptor (AR) pathway inhibitors, has changed the paradigm in the management of such patients. Methods: This is a clinical descriptive review. Using the key words “Non-metastatic castration resistant prostate cancer” and “Androgen receptor targeted agents” in PubMed database, we reviewed and summarized the current literature about the definition, diagnosis and treatment of nmCRPC. We highlight the results of recent Phase III trials that showed significant impact on the outcomes of treatment of nmCRPC. Primary outcome was Metastasis-free Survival (MFS) and secondary outcomes included were Overall Survival (OS) among others as well as rates of Adverse Events (AEs). Development and Discussion: The SPARTAN trial showed a median MFS for patients treated with apalutamide plus Androgen Deprivation Therapy (ADT) of 40.5 months compared to 16.2 months for patients who received ADT plus placebo [hazard ratio (HR) 0.30; 95% confidence interval (CI) 0.24-0.36; p < 0.0001). Apalutamide also showed a statistically significant benefit in OS compared to placebo, with a median of 73.9 versus 59.9 months [HR: 0.78 (95% CI: 0.64-0.96), p: 0.016]. In the PROSPER trial, the median MFS for the enzalutamide group was 36.6 months compared to 14.7 months for the placebo group [HR: 0.29 (95% CI: 0.24-0.35), p < 0.0001]. OS was significantly higher in the enzalutamide group (67 versus 56.3 months in the placebo group), reaching the statiscal significance [HR: 0.73 (95% CI: 0.61-0.89), p: 0.001]. The ARAMIS trial showed a median MFS for patients treated with darolutamide plus ADT of 40.4 months compared to 18 months for the placebo group [HR: 0.41; (95% CI: 0.34-0.5); p<0.001]. The benefit of darolutamide in OS was also clear, with a HR of 0.69 (95% CI: 0.53-0.88), p: 0.003]. Conclusions: Apalutamide, enzalutamide and darolutamide have demostrated an increase in MFS and OS with a good safety profile in patients with high risk nmCRPC. There are no recommendations in favor of any drug so far, comparative studies are needed.