Background: Cabazitaxel (C) improves overall survival and has been approved in second line chemotherapy for patients (pts) with metastatic castrate resistant PCa. We hypothesized that C is a radiosensitizer and performed a phase I trial of weekly C with standard IMRT and ADT for pts with high risk localized PCa. Methods: Conventional “3 + 3” design. Pts with newly diagnosed high risk PCa defined as either Gleason score (GS) 8 – 10, or T3/T4 with GS 7, or PSA > 20 with GS 7 are eligible. Dose escalation occurred only after all the cohort pts completed weekly C ( 4 cohorts at the dose of 4, 6, 8 and 10 mg/m²) and the total planned dose IMRT. ADT was started two months prior to C and IMRT then continued on for a total of 28 months. Daily bicalutamide started within 1 day to 2 weeks prior to LHRH agonist therapy and stopped on the last day of IMRT for approximately 4 month duration. IMRT is delivered to a total dose of 75.6 Gy at 1.8 Gy daily fraction for 8.5 – 9 wks. The primary objective of this study was to determine the safe dose of the combination of weekly C with IMRT and ADT. Results: At present, 9 pts of mean age 66 yrs (range 53 – 82), T2 - T4; mean PSA 89 (range 4 – 253); and median GS 9 (GS 8 – 10) completed the chemo-radiation therapy. Grade 3 dose-limiting toxicites in the first two pts at the 8 mg/m² C dose level were diarrhea and elevated transaminase, thus the maximum tolerable dose (MTD) of C with IMRT was determined to be 6 mg/m². In this dose level, there were grade 2 toxicities only (diarrhea, hypophosphatemia and leukopenia at the rate of 50, 17 and 17% respectively). One pt finished 2 year observation without long term toxicities. An expansion cohort at 6 mg/m2 is ongoing. Conclusions: Concurrent weekly C with current standard IMRT is feasible with no unexpected toxicity. In combination with IMRT and ADT, the MTD of weekly C is 6 mg/m2 in pts with newly diagnosed high risk PCa. Clinical trial information: NCT01420250.