Fig. 2: Incidence of adverse events associated with ARIs reported in the final analyses of the A SPARTAN [42], B PROSPER [45], and C ARAMIS [48] clinical trials.

A SPARTAN: at final analysis, median follow-up was 52.0 months; median treatment duration in apalutamide arm was 32.9 months and in the placebo arm was 11.5 months. B PROSPER: at final analysis, median follow-up was 48.0 months; median treatment duration in enzalutamide arm was 33.9 months (95% CI 0.2–68.8) and in the placebo arm was 14.2 months (95% CI 0.1–51.3). ^aFatigue events included asthenia. ^bMusculoskeletal events included back pain, arthralgia, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal stiffness, muscular weakness, and muscle spasms. ^cFracture events included bone and joint injuries. ^dHypertension events included hypertensive retinopathy, increased blood pressure, systolic hypertension, and hypertensive crisis. ^eEvents of cognitive and memory impairment included disturbance in attention, cognitive disorders, amnesia, Alzheimer’s disease, dementia, senile dementia, mental impairment, and vascular dementia. ^fCardiovascular events included hemorrhagic central nervous system vascular conditions, ischemic central nervous system vascular conditions, and cardiac failure. ^gEvents of ischemic heart disease included myocardial infarction and other ischemic heart disease. ^hRash events included maculopapular rash, generalized rash, macular rash, papular rash, and pruritic rash. ⁱLoss-of-consciousness events included syncope and presyncope. ^jAngioedema events included urticaria, eyelid edema, periorbital edema, swollen tongue, swollen lip, face edema, laryngeal edema, and pharyngeal edema. ^kHepatic disorders included hepatic failure, fibrosis, cirrhosis, and other liver damage-related conditions, and hepatitis and liver-related investigations, signs, and symptoms. ^lThrombocytopenia events included decreases in platelet count. C ARAMIS: at final analysis, median follow-up was 29.0 months; median exposure in darolutamide arm was 18.5 months and in the placebo arm was 11.6 months. ^mCombined term comprising MedDRA terms of any fractures and dislocations, limb fractures and dislocations, skull fractures, facial bone fractures and dislocations, spinal fractures and dislocations, and thoracic cage fractures and dislocations. ⁿCombined term comprising MedDRA terms of asthenic conditions, disturbances in consciousness, decreased strength and energy, malaise, lethargy, and asthenia. ^oCombined term comprising MedDRA terms of rash, macular rash, maculopapular rash, papular rash, and pustular rash. ^pOne additional incidence of seizure occurred in the darolutamide group during the open-label period, in a patient with a history of epilepsy. ^qMedDRA High Level Group term. ^rAlthough the incidence of cardiac arrhythmia was higher with darolutamide than with placebo, both a history of cardiac arrhythmia and electrocardiogram abnormalities were present to a greater extent in the darolutamide group at baseline, as observed at primary analysis. ARI androgen receptor inhibitor, CI confidence interval, MedDRA Medical Dictionary for Regulatory Activities.