The novel androgen receptor inhibitors have been shown to be effective in advanced prostate cancer (PCa) in the metastatic castrate-sensitive (CSPC), metastatic castrate-resistant (CRPC) and high-risk, non-metastatic (nmPC) settings. We conducted a study level meta-analysis to explore and compare toxicities from these novel agents which may improve treatment selection.
MEDLINE and PubMed databases were searched for randomised controlled trials of apalutamide, darolutamide and enzalutamide using pre-specified keywords, inclusion and exclusion criteria. The risk of toxic death, grade 3 or 4 adverse events (AEs) and treatment discontinuation owing to AEs was analysed using weighted risk ratio (RR) calculations, with corresponding 95% confidence intervals (CI). The most common toxicities identified from the trials and toxicities of interest such as falls and seizures were reviewed. Subgroup analysis was performed to compare between the CSPC, CRPC and nmPC settings.
Ten trials with a total of 6407 patients were included. Compared to control, there was similar risk of toxic death (RR 1.31, CI 0.81-2.1, p=0.23) and grade 3 or 4 AEs (RR 1.05, CI 0.86-1.27, p=0.6). Treatment discontinuations owing to AEs were reported in 9% (RR 1.25, CI: 1.01-1.55, p=0.04). Fatigue, hypertension, falls and hot flushes were significantly more common, in particular hypertension (RR 1.59, CI: 1.16-2.17, p=0.0091) and falls (RR 1.63, CI 1.21-2.19, p=0.005). The risk of seizures was not increased. Grade 3 or 4 AEs were significantly more common in the nmPC setting (RR 1.28, CI 1.16-1.40, p=0.007).
The novel anti-androgens appear safe in advanced PCa with no substantive increased risk of toxic death or grade 3 and 4 adverse events. However, toxicities such as falls and hypertension are common, as well as treatment discontinuation owing to AEs. Analysis of specific toxicities of each agent and treatment setting may provide insight into improved treatment selection in the future.