Background: The humanized monoclonal IgG2 antibody abituzumab inhibits αv integrins expressed on CRPC cells, tumor vessels, and osteoclasts involved in bone (B) metastasis. It showed antitumor effects in in vivo CRPC models and was well tolerated in a phase 1 study in mCRPC pts previously treated with docetaxel. Methods: PERSEUS is an exploratory double-blind trial with 180 pts randomized 1:1:1 to placebo, abituzumab 750, or 1,500 mg i.v. given every 3 weeks in addition to standard of care. Eligible pts had radiologic disease progression (rPD) of B lesions <28 days prior to randomization. Pts were treated until rPD in either B or soft tissue (ST) lesions, skeletal event, death, or unacceptable toxicity. Primary endpoint was progression-free survival (PFS). In addition, overall response (OR, RECIST 1.0) and safety were assessed. Results: Baseline characteristics were balanced across arms. In pts treated with placebo, abituzumab 750, and 1500 mg, median PFS (ITT) was 3.3 (95% CI: 2.8, 4.8), 3.4 (95% CI: 2.8, 5.6; HR = 0.89 [95% CI: 0.57, 1.39]), and 4.3 months (95% CI: 2.8, 6.6; HR = 0.81 [95% CI: 0.52, 1.26]), respectively. Progression occurred in 72, 68, and 65% of pts, respectively, incl. B lesion progression observed in 42% of pts in the control arm and in 23% of pts in each abituzumab arm. Of 74 OR-evaluable pts with confirmed ST lesions at baseline, 2 achieved partial responses (placebo: 1/28 pts; abituzumab 1500 mg: 1/24 pts). Treatment-emergent adverse events (TEAEs) occurred in 92, 85, and 88% of pts in the placebo, abituzumab 750, and 1500 mg arms, respectively, incl. serious TEAEs in 27, 22, and 23% and TEAEs with fatal outcomes in 3, 3, and 5% (treatment-related AE: 1 pt in the placebo arm). Conclusions: Median PFS with abituzumab 1500 mg was above the duration observed with 750 mg or placebo. Compared with placebo, pts receiving abituzumab experienced B progression less frequently. Considering these favorable trends, further investigation of abituzumab efficacy is needed. Its previously observed safety profile was confirmed. Clinical trial information: NCT01360840.