Background: Angiogenesis appears to play critical role in the progression of mCRPC. Previously we have shown anti-tumor activity in mCRPC with the combination of D, thalidomide (T), A and P (Ning JCO 2010). We hypothesized that combining R, an analogue of T, with A, D and P would have a more favorable toxicity profile and similar anti-tumor activity. 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 CT's are at baseline, after C5, and then every 6C or earlier if needed. Results: 28 of a planned 51 pts have been enrolled. Pt characteristics include: median age 65.5 [51-78], Gleason score 8 [67.9% 8-10, 32.1% 6-7], on-study PSA 94.3 ng/mL [9.2-3520], and pre-study PSA doubling time 1.43 months [0.52-4.07]. Median C number was 8 [1-21]. 2/28 pts were off study due to clinical or radiographic progression. 26 pts remain on study. 22/24 (91.7%) and 20/24 (83.3%) pts who have completed ≥ 4C had PSA- decline of ≥ 50% and ≥ 75%, respectively. 14 pts with measurable disease were evaluable with 2 CRs (1 unconfirmed), 9 PRs (2 unconfirmed), and 3 SDs (a 78.6% overall RR). Grade ≥ 3 toxicities include neutropenia (16/28), anemia (6/28), thrombocytopenia (3/28), hypertension (1/28), and infection (2/28). 1/28 pts had febrile neutropenia. 8/28 pts (28.6%) developed grade 2 osteonecrosis of the jaw (ONJ), defined as bone death on dental exam, higher than 18.3% as reported by Ning. 5/8 had concomitant and 2/8 pts had history of bisphosphonate use. Conclusions: Combined therapy with anti-angiogenic agents R and A, plus D and P is associated with high response rates, 91.7% in PSA and 78.6% in measurable disease in mCRPC pts, 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.