OBJECTIVES: Patients with mCRPC are at risk of experiencing skeletal-related events (SREs), defined as pathologic fracture, spinal cord compression, and the need for radiotherapy or surgery to bone. We examined the immediate impact of an SRE on patients’ HRQoL. METHODS: Data were obtained from the AFFIRM study, a phase 3 trial of enzalutamide vs. placebo in patients with mCRPC. Only patients experiencing any type of SRE were included in the analysis (n=284). For patients with multiple SREs, only the first event was used. HRQoL was assessed at baseline and at fixed intervals throughout the study until treatment discontinuation using the FACT-P (Functional Assessment of Cancer Therapy–Prostate) instrument. We used linear mixed-effects models to model each patient’s longitudinal trajectory of FACT-P outcomes before the first SRE and to estimate how far the post-SRE value of HRQoL deviated from that trajectory. RESULTS: SREs were associated with a deterioration of HRQoL with an adjusted mean change of -6.93 (95% CI: [-9.92; -3.95]) of the FACT-P total score for any SRE. The largest impact was observed in subjects with spinal cord compression, which induced a mean decrease in the FACT-P total score of -9.68 (95% CI: [-16.10; -3.27]); pathological bone fractures and radiation or surgery to bone determined changes in FACT-P total score of -7.61 (95% CI: [-16.79; 1.56]) and -6.68 (95% CI: [-10.25; -3.11]), respectively. The standardized effect size was moderate (any SRE: -0.32; spinal cord compression: -0.49; pathological bone fracture: -0.35; radiation or surgery to bone: -0.30). CONCLUSIONS: Consistent with previous analyses in metastatic prostate cancer [Weinfurt K.P., et al. Annals of Oncology 2005;16: 579–584], our findings demonstrate that SREs lead to significant functional declines in patients’ daily lives. Therefore, any therapy reducing or delaying the occurrence of SREs should also reduce the effects of SREs on HRQOL.