Background: cfDNA can be utilized to evaluate androgen receptor (AR) alterations in metastatic castrate resistant prostate cancer (mCRPC) patients. Given the role of androgen receptors in the pathophysiology of PC, mutations in the AR gene can have important implications regarding prognosis and treatment. The goal of this research was to evaluate associations between certain PC treatments and AR mutations. Methods: Treatment and demographic data from 121 patients diagnosed with PC was collected including genetic data derived from the Guardant360 test (Guardant Health, Redwood City, CA). AR alterations were compared among race, treatment history, and other somatic alterations. Results: 52.9% (n = 64) of the mCRPC pts evaluated had an AR alteration. Of the pts with AR alterations, 43.8% (n = 28) had AR amplification (amps), 37.5% (n = 24) had AR mutations (muts), and 18.8% (n = 12) had both. AR muts included: T878A (n = 15), H875Y (n = 8), W742C (n = 11), AR L702H (n = 7), and others. AR alterations comprised on average about 7% of tumoral cfDNA. To better understand the relationship between AR alterations and other commonly detected cfDNA aberrations, associations between BRAF (27.3%), TP53 (44.6%), and MYC (19.0%) and AR were assessed. Among these genes, P53 alterations were all Muts. MYC (n = 21) and BRAF (n = 27) alterations were predominantly amps though muts were also detected in MYC (n = 3) and BRAF (n = 9). P53 muts were not significantly associated with AR alterations. BRAF and MYC alterations significantly associated with AR alterations (p = 0.0012 and p = 0.0223). Pts were re-tested upon disease progression; among these patients, 52.2% (n = 24) had an increase in overall mut burden. Conclusions: AR alterations in cfDNA impact both disease progression and response to therapy. Co-segregation of AR, BRAF, and MYC alterations may also have significant prognostic and therapeutic implications. Further research, a larger sample size, and longitudinal assessment are needed to further elucidate associations between disease progression and treatment response to the development of somatic alterations over time in mCRPC.