Androgen deprivation therapy (ADT) is the cornerstone treatment of prostate cancer. However, androgen independent status inevitably develops over time, leading to the castration resistant prostate cancer (CRPC) phenotype. Several treatments, including chemotherapy agents and novel hormonal agents, have been shown to improve outcome of patients with metastatic CRPC (mCRPC). Recently, two randomized controlled trials (RCT) demonstrated increased metastasis free survival (MFS) with apalutamide (SPARTAN Trial) and enzalutamide (PROSPER Trial) in nmCRPC patients, but failed to demonstrate a statistically significant increase in overall survival (OS).
A meta-analysis at trial level was performed including published data from SPARTAN and PROSPER trials. Efficacy data was investigated and retrieved to calculate hazard-ratio (HR) for OS and MFS, with 95% CI. The safety profile was investigated for fatal adverse events (FAEs) and the relative risk (RR) calculated, with 95% CI. Random-effects or fixed-effects models were performed on the basis of the heterogeneity of included studies. A p-value <0.05 was considered statistically significant.
A total of 2,602 patients were included for efficacy (intention-to-treat [ITT] population) and 2,596 for safety analysis (per-protocol population). 1736 patients received novel hormonal agents (806 apalutamide and 930 enzalutamide) and 866 placebo. Efficacy analysis confirmed improved MFS (HR 0.29; 95% CI, 0.25-0.33; p < 0.0001) and also demonstrated a significant increase in OS (HR 0.76; 95% CI, 0.59-0.76; p = 0.03). Safety analysis showed an increased risk of FAEs (HR 5.24; 95% CI, 1.89-14.55) with apalutamide and enzalutamide, however this should be interpreted with caution due to the much longer exposure time to the experimental arm compared to placebo.
This meta-analysis reinforces the benefit of MFS and demonstrated a significant increase in OS with novel hormonal agents apalutamide and enzalutamide in patients with nmCRPC. Further analysis will be necessary to determine the breakdown of treatment-related versus –unrelated deaths.
Clinical trial identification
Legal entity responsible for the study
Daniel Vargas Pivato de Almeida.
Has not received any funding.
A.K. Morgans: Honoraria: Sanofi, Janssen, Genentech, AstraZeneca. S. Srinivas: Data and Safety Monitoring Committee: Pfizer; Advisory Board: Jansen. T. Dorff: Advisory board: Janssen; Promotional speaker: Exelixis, Prometheus; Consulting: Bayer, EMD Serono. E.Y. Yu: Honoraria: Janssen. F.A. Schutz: Site Principal investigator: Roche, BMS, MSD, Astra Zeneca; Speaker's bureau: Sanofi, AstraZeneca, Bayer, Janssen, Astellas, BMS, Pfizer, Roche; Advisory board: Bayer, Janssen, Astellas, Novartis, Roche, MSD. All other authors have declared no conflicts of interest.