e15122 Background: The majority of patients who die of prostate cancer have metastatic castration-resistant disease (CRPC). Available therapies provide modest prolongation of survival measured in months. We have previously demonstrated that the use of BB2r targeted radiation therapy (TRT) using 177Lu-DOTA-8-AOC-BBN (7-14)NH2 in combination with chemotherapy suppressed tumor growth in SCID mice in both flank and intra-tibial models employing PC-3 cells; however, significant bone loss resulting in tibial fracture was a predominant deterrent to prolonged subject survival. Since zoledronic acid (ZA) is effective in treatment of diseases with pathologically increased osteoclast-mediated bone resorption, including metastatic bone disease, we postulated that by adding ZA, tibial fractures can be delayed resulting in improved outcomes. Methods: In a randomized study, SCID mice received intra-tibial inoculation of PC-3 cells on day (-7). Therapy (Table) was started on day(+1). Daily weight and body condition scores (BCS) and weekly radiographs were collected. Subjects were given two “21day” cycles. Subjects were removed upon reaching predetermined endpoint criteria including tibial fracture, BCS of ≤-2, significant weight loss. Results: At study termination(Day 86) 83% of the mice in Arm C(TRT+CT+ZA) and 80% of mice in Arm A(CT+ZA) had survived as compared to 29% of the mice in Arm B(CT+TRT). Health status of mice in Arm B consistently declined over the study duration, with subject removal beginning at Day 20resulting from stated endpoint criteria. Conclusions: ZA used in combination with BB2rTRT and chemotherapy is effective in prolonging short term survival in a preclinical model of CRPC. Further studies are required to ascertain if the addition of BB2r TRT to a ZA+chemotherapy regimen results in significantly improved outcomes. Therapy/day Mon Tue Wed Thu Fri Sat Sun Arm A (n=10) CT ZA CT CT CT ZA CT Rest Rest Arm B (n=7) CT CT CT TRT CT CT Rest Rest Arm C (n=6) CT ZA CT CT TRT CT ZA CT Rest Rest Control (n=2) A therapy cycle was given every 3 weeks; Chemotherapy (CT): docetaxel(ip) D1,8,15/capecitabine(po) D1-5,8-12;ZA:subcut 100mcg/kg D1,4,8,11,15,18; TRT(ip) D3,10,17.