Background: Cross resistance between androgen-receptor targeting therapies (ARTs) (abiraterone acetate plus prednisone [ABI + P] or enzalutamide [ENZ]) for treatment of metastatic castration-resistant prostate cancer (mCRPC) may affect responses to second ART (ART2). Objective: To establish treatment duration and prostate-specific antigen (PSA) response of ART2 in real-world mCRPC patients treated with or without other life-prolonging drugs (LPDs; ie, docetaxel, cabazitaxel, or radium-223) between ART1 and ART2. Design, Setting, and participants: Castration-resistant prostate cancer patients, diagnosed between 2010 and 2016 were retrospectively registered in Castration-resistant Prostate Cancer Registry (CAPRI). Patients treated with both ARTs were clustered into two subgroups: ART1 > ART2 or ART1 > LPD > ART2. Outcome measurements and statistical analysis: Outcomes were >= 50% PSA re- sponse and treatment duration of ART2. Descriptive statistics and binary logistic regression after multiple imputations were performed. Results and limitations: A total of 273 patients were included with a median follow-up of 8.4 mo from ART2. Patients with ART1 > ART2 were older and had favourable prognostic characteristics at ART2 baseline compared with patients with ART1 > LPD > ART2. No differences between ART1 > ART2 and ART1 > LPD > ART2 were found in PSA response and treatment duration. Multivariate analysis suggested that PSA response of ART2 was less likely in patients with visceral metastases (odds ratio [OR] 0.143, p = 0.04) and more likely in patients with a relatively longer duration of androgen-deprivation treatment (OR 1.028, p = 0.01) and with ABI + P before ENZ (OR 3.192, p = 0.02). A major limitation of this study was missing data, a common problem in retrospective observational research. Conclusion: The effect of ART2 seems to be low, with a low PSA response rate and a short treatment duration irrespective of interposed chemotherapy or radium-223, especially in patients with short ...