Background: Angiogenesis may play a critical role in the progression of mCRPC. Previously we have shown the potent anti-tumor activity of the combination of D, Thalidomide (T), A, and P in mCRPC (Ning JCO 2010). We hypothesized that combining R, an analogue of T, with A, D and P would have a more favorable efficacy/toxicity profile. Methods: All pts had chemotherapy-naïve progressive mCRPC. 6 pts were treated with R at 15 and 20 mg prior to doses at 25 mg. Treatment is 75 mg/m2 D, 15 mg/kg A every 21 days as one cycle (C), plus 25 mg R for 14 days with daily 10 mg P and enoxaparin. After grade 3 neutropenia was seen in > 80% of pts in all cohorts, the protocol was amended to include prophylactic pegfilgrastim. PSA is tested each C with imaging after C2 and then every 3C. Dental exams with mandible CTs are at baseline, after C5, and then every 6C or earlier if needed. Results: 32 of the planned 51 patients have been enrolled. Characteristics were: median age 66 [51-82], Gleason score 8 [68.8% 8-10, 31.2% 6-7], on-study PSA 136 ng/ml [9.2-3520], and pre-study PSA doubling time 1.43 months [0.52-4.07]. Median treatment Cs was 11 [2-26] as of this analysis. 3/32 patients came off study due to clinical and radiographic progression. 29 patients remain on study; 29/32 (90.6%) and 24/32 (75%) patients who have completed ≥2 cycles had PSA declines of ≥50% and ≥75%, respectively. Of 17 patients with measurable disease there were 1 CR, 13 PR, and 3 SDs (82.4% overall RR). Grade ≥ 3 toxicities included neutropenia (16/32), anemia (6/32), thrombocytopenia (3/32), weight loss (1/32), hypertension (1/32), and infection (4/32). 1/32 pts had febrile neutropenia. 2/32 pts had perianal fistula. 10/32 pts (31.3%) had grade 2 osteonecrosis of the jaw (ONJ), defined as bone death on dental exam; 6/10 pts had concomitant and 3/10 pts had a history of bisphosphonate use. Conclusions: Combined therapy with anti-angiogenic agents A and R, plus D and P is associated with high response rates, 90.6% in PSA and 82.4% in measurable disease in mCRPC, with manageable toxicities. Further study is underway to characterize the activity and to explore the high incidence of ONJ, including the possibility of ascertainment bias.