PURPOSE: Men with castrate resistant prostate cancer have limited treatment options. Although luteinizing hormone-releasing hormone agonists are in the same class, they are slightly different in their pharmacology. We determined whether rechallenging patients with prostate cancer, who were receiving a luteinizing hormone-releasing hormone analogue but had progression, with a different luteinizing hormone-releasing hormone analogue (goserelin or leuprolide acetate) would result in a prostate specific antigen response. Secondary objectives were to calculate the PSA response and determine whether sequence order impacted the response. MATERIALS AND METHODS: We performed a retrospective, ethics approved review of the records of patients with prostate cancer at multiple institutions who received a luteinizing hormone-releasing hormone analogue (goserelin or leuprolide acetate), experienced progression, as measured by 2 consecutive prostate specific antigen increases, and were rechallenged with the other analogue (goserelin or leuprolide acetate). Prostate specific antigen and relevant clinical data were obtained and statistical analysis was done. RESULTS: Of 39 available men 27 (69%) had decreased prostate specific antigen after 3 months of switching regimens. The median change in prostate specific antigen was -1.5 (IQR -10.0, 0.8), indicating a statistically significant decrease (p=0.01). The median percent prostate specific antigen change for leuprolide acetate to goserelin was -69.3% (IQR -81.5, 26.2) and for goserelin to leuprolide acetate it was -6.4% (IQR -61.7, 21.8, p=0.05). Median time to a subsequent prostate specific antigen increase was 5.2 months (95% CI 3.5-17.4). CONCLUSIONS: Prostate specific antigen decreased after switching luteinizing hormone-releasing hormone therapies. This decrease appeared most significant in the group that switched from leuprolide acetate to goserelin. The duration of response after switching was approximately 5 months. The study is limited by its retrospective nature but should encourage prospective evaluation of this observation.