Background: Vascular endothelial growth factor (VEGF)-mediated angiogenesis and insulin-like growth factor (IGF-IR)-mediated signaling contribute to mCRPC growth. CIX and RAM are fully human IgG1 human monoclonal antibodies targeting IGF‑IR and VEGF receptor-2 (VEGFR-2) respectively. We investigated the safety and efficacy of CIX or RAM in combination with M + P in mCRPC pts with PD on DCT. Methods: Eligible pts had mCRPC and PD during/within 120 days of DCT, ECOG PS 0-2, PSA ≥ 2 ng/mL, and adequate organ function. All pts received M 12 mg/m² IV every 3 weeks (w) + P 5 mg PO BID for up to 12 cycles and were randomized to either CIX 6 mg/kg or RAM 6 mg/kg IV q w. Tumor assessments were after the first 3 cycles and then q6w. Primary endpoint was composite progression-free survival (cPFS: either RECIST PD, bone scan PD or new skeletal events). Other endpoints included safety, response and overall survival (OS). Sample size was based on a targeted 50% increase in median (mdn) cPFS from 2.6 months (m) to 3.9 m. Results: 132 pts were treated; 66 each to CIX or RAM. Mdn age and baseline PSA was 65 yr and 129 ng/mL for pts treated with CIX and 68 yr and 111 ng/mL for RAM. Involvement of sites other than bone was CIX: 79% and RAM: 70%. The most frequent Grade ≥3 related adverse events for CIX/M/P: fatigue 17%, leukopenia 12%, and neutropenia 8%, and for RAM/M/P: leukopenia 8%, neutropenia 8% and hypertension 8%. Left ventricular dysfunction/CHF: 12% for CIX (0% G3) and 23% for RAM (8% G3). Mdn number of Rx cycles were 5 for CIX and 6 for RAM. Mdn follow-up was 22.7 m for CIX and 21.8 m for RAM. PSA response was 18.4% (8.8-32% 95% CI) on CIX and 22.0% (11.5-36% 95% CI) on RAM. Mdn cPFS and OS were 4.1 m (3.0-5.6 m 95% CI) and 10.8 m (6.5-13.0 m 95% CI) for CIX and 6.7 m (4.5-8.3 m 95% CI) and 13.0 m (9.5-16.0 m 95% CI) for RAM. Conclusions: CIX/M/P and RAM/M/P were reasonably tolerated and achieved the primary endpoint. Preliminary cPFS and OS of RAM/M/P appear encouraging; sustained disease control was observed in pts on both rx arms. Correlation of serum markers of IGF and VEGF activity with clinical endpoints is planned.