Introduction: Androgenic deprivation therapies have been linked to the development of metabolic syndrome (MS) and cardiovascular diseases, which may lead to a poorer survival in patients with metastatic Castration-Resistant Prostate Cancer (mCRPC). We aimed to analyze whether some cardiovascular or neurological disorders, together with other medical and urological complications, may have an effect on survival outcomes, at baseline and during treatment from patients treated with androgen pathway inhibitors (API). Material and Methods: A retrospective study of a consecutive series of patients diagnosed with mCRPC between 2010 and 2018 treated with API in the first line setting in a single center. Results: Seventy-three patients met the inclusion criteria. Baseline prognostic factors associated with worse survival were diabetes mellitus (DM) with insulin needs compared to patients without DM hazard ratio (HR) = 0.19, p = 0.025, hypertension (HTN) (HR = 0.46, p = 0.035), and a history of stroke (HR = 0.16, p < 0.001). However, previous history of hypercholesterolemia, arrythmias, and cognitive disorders did not result in a significant worsening on survival. During treatment, patients who developed de novo HTN had the best progression free survival (PFS) (HR = 0.38, p = 0.048) and overall survival (OS) (HR 0.08, p = 0.012) compared with patients with previous HTN. Other factors related to worse outcomes included the presence of heart failure (HR = 0.31, p = 0.001), the requirement for major opioids for pain relief (HR = 0.33, p = 0.023), and the presence of bilateral ureterohydronephrosis (HR = 0.12, p = 0.008). Conclusions: Some comorbidities may be strongly involved in patient outcomes when receiving API for mCRPC. In this sense, collaborative networking between specialists and caregivers treating prostate cancer (PC) patients should be recommended, focusing on MS features, cardiovascular and neurological disorders in order to anticipate medical and surgical complications.