LAUSR

Abstract Background Three recent RCT (Spartan, Prosper and Aramis) have demonstrated improved metastasis-free survival with new ARi Apalutamide (A), Enzalutamide (E) and Darolutamide (D), respectively, vs placebo (pl) in nmCRPC. We conducted a meta-analysis of RCT to evaluate the safety of ARi. Methods Random-effects meta-analysis was performed to describe pooled odds ratio (OR) vs pl and presence of heterogeneity in the effect among RCT. Network meta-analysis was performed to describe OR of indirect comparisons. Results 4104 patients were included in safety analysis. Many adverse events (AEs) (falls, fractures, fatigue, nausea, diarrhea, hypertension, rash) showed a significant difference in the incidence in patients receiving pl, mostly higher in the Spartan trial. The use of ARi was associated with an higher risk of developing selected AEs compared to pl: serious AEs (OR 1.28, 95%CI 1.10-1.50); falls (OR 1.81, 95%CI 1.40-2.34); fractures (OR 1.58, 95%CI 1.11-2.23); fatigue (all grades OR 2.00, 95%CI 1.68-2.39; severe OR 2.21, 95%CI 1.06-4.60); rash (OR 4.90, 95%CI 3.24-7.41); diarrhea (OR 1.24, 95%CI 1.00-1.54); hypertension (all grades OR 1.55, 95%CI 1.25-1.92; severe OR 1.44, 95%CI 1.08-1.92); dizziness (OR 1.67, 95%CI 1.26-2.21), mental impairment (OR 1.73, 95%CI 1.13-2.66). Significant heterogeneity in the effect among ARi was found for falls (D better than E: OR 0.29, 95%CI 0.14-0-60; D better than A: OR 0.48, 95%CI 0.25-0.91); fatigue all grades (D better than E: OR 0.59, 95%CI 0.39-0.88; A better than E: OR 0.61, 95%CI 0.44-0.84) and severe (D Better than E: OR 0.10, 95%CI 0.02-0.60); hypertension (D better than E: OR 0.51, 95%CI 0.27-0.98; A better than E: OR 0.53, 95%CI 0.31-0.92); mental impairment (D better than E: OR 0.15, 95%CI 0.04-0.58; D better than A: OR 0.24, 95%CI 0.06-0.90). No significant heterogeneity was found for other AEs. Conclusions With the limitations of the network meta-analysis, our findings suggest that the use of ARi in nmCRPC is associated with a statistically significant increased risk of developing selected AEs according to the type of agent used. Potential specific toxicities should be considered before starting ARi in nmCRPC. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure A. Altavilla: Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Janssen. M. Di Maio: Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Merck Sharp & Dohme; Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Janssen; Honoraria (self): Takeda; Research grant / Funding (institution): Tesaro. M. Tucci: Honoraria (self): Astellas; Honoraria (self): Janssen; Honoraria (self): Bayer; Honoraria (self): Sanofi. U. De Giorgi: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): roche; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy: Astellas; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol Meyer Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer. All other authors have declared no conflicts of interest.