Background: AA and ENZ are both approved for the treatment of mCRPC. Understanding the early impact of these treatments on various domains of cognitive function, depression and fatigue would lead to optimisation of treatment selection and promote supportive care planning in this patient group. Methods: The study was conducted at 12 UK centres to assess the impact of AA or ENZ on cognitive function and fatigue in mCRPC patients. Cognition was assessed using the CANTAB assessment tool at baseline prior to initiation of AA or ENZ and then at 3, 4 and 6 months. Patient reported outcomes (PROs) were also collected at these timepoints using the FACT-Cog, FACT-F and PH9-Q questionnaires. Results: Data from 253 patients at baseline (141 AA; 112 ENZ), were analysed with a median age 74 (52-92). Previous docetaxel had been received by 49% of patients. Sample size at 3-months was 184 (95 AA; 89 ENZ) and was 131 at 6-months (67 AA; 64 ENZ). After controlling for baseline, there was no difference between AA and ENZ in mean composite cognitive outcome (3-months p = .553, 6-months p = .198) or in the individual components for Spatial Working Memory, Rapid Information Processing, or Spatial Information Processing. However, the Reaction Time Task difference was significant at 3-months (p=.009) and 6 months (p = .037). The ANCOVA suggests that at 6-months the gap between ENZ and AA has significantly widened and this is due to marginally poorer performance in ENZ and marginally improved performance in AA. When comparing individual components of the PROs such as the mean fatigue changes (FACT-F scale) between baseline and each timepoint, there was significant deterioration in the ENZ (p < .001) but not the AA group, with a statistically significant difference in mean fatigue between AA and ENZ at 3-months (p < .001), and at 6-months (p < .001). Mean PHQ-9 score (for depression) showed increased levels of depression in both groups, but with outcomes significantly poorer in ENZ at 3-months (p = .022) and 6-months (p = .020) compared to AA. Mean PCA (Perceived cognitive ability) and CFO (comments from others) was significantly poorer in ENZ at 3-months (p <.001) and at 6-months (p <.001) with no significant difference between groups in (PCI) perceived cognitive impairment. Conclusions: This study shows that whilst composite cognitive outcome is comparable in mCRPC patients treated with AA or ENZ at 3 and 6 months, patients on ENZ report more fatigue, depression and deterioration in perceived cognitive ability and have a slower reaction time when compared to AA. This is an important consideration for treatment optimisation and ensuring supportive strategies for the patients when using these drugs keeping in perspective the cognitive function assessment at baseline and subsequently on treatment.