Background: Novel AA agents, such aspalutamide (Apa), enzalutamide (Enza) and darolutamide (Daro) are approved for the treatment of nmCRPC. In clinical trials, they were associated with AEs such as fatigue, fractures and falls. This study aimed to describe the real-world incidence of AEs among nmCRPC patients who initiated treatment with AA agents. Methods: Claims from Optum Clinformatics Data Mart, a large single-payer claims database were used to retrospectively identify adult males with prostate cancer (PC), evidence of castration, absence of metastases codes and >1 claim for AA therapies Apa and Enza (index date) from Jan 2017 through Dec 2019. Daro, a more recently approved AA, was not included due to lack of data. Incidence of central nervous system (CNS) (including but not limited to fatigue, falls and cognitive impairment) and any AE (fracture, rash, hypertension among others) were estimated and Kaplan-Meier analyses were used to quantify the median time from therapy initiation to clinical event occurrence. Multivariable Cox-proportional hazards model was used to identify clinical event predictors. A washout of previous AE events in the 1-year baseline was applied to identify true incident events. Results: A total of 605 patients (156 Apa and 449 Enza) were included in the study. The majority were ≥65 yrs (94.0%), white (56.0%), resided in the south (47.1%), and had Medicare insurance (86.4%). Almost all were medically castrated (99.0%) and mean Charlson Comorbidity Index (CCI) Score was 2.28. Incidence rates of all clinical events and CNS-related events were high (71.2% and 46.1%, respectively) with no major differences between Apa and Enza (Table). The median time from Apa or Enza treatment initiation to any clinical event was 71 and 64 days, respectively, and 282 and 209 days for CNS-related events, respectively. Significant predictors of having any events included age >75 yrs and high CCI score. Similar predictors were found for any CNS events. Conclusions: More than 70% of Apa and Enza treated nmCRPC patients had at least 1 clinical AE. Given the lack of a control cohort, further study is needed to assess whether these events are related to AAs or represent inherent risks of these events in the underlying population of largely older men with advanced PC. Future studies are warranted with all approved agents including Daro.

*CNS related events include amnesia, anxiety, ataxia, cognitive disorders, confusion, convulsion, dizziness, falls, fatigue, headache, hallucinations.