Background: Ra-223, a bone-targeted alpha therapy, is a well-tolerated treatment option that prolongs survival in patients (pts) with symptomatic mCRPC to bone. Docetaxel targets microtubule trafficking improving survival in the mCRPC and metastatic hormone-sensitive settings. We hypothesized that simultaneously targeting the tumor and bone compartment yields superior outcomes than targeting either alone. We previously determined the dose and schedule of co-administering Ra-223 + docetaxel in a randomized phase I/IIa trial. The combination appeared to have superior declines in prostate specific antigen (PSA) and bone markers, delayed PSA progression, and was better tolerated (with adjusted dose/schedule) relative to standard docetaxel alone. We are now conducting a phase III study. Methods: DORA is an open-label investigator-initiated phase III study sponsored by Memorial Sloan Kettering Cancer Center and managed by the Prostate Cancer Clinical Trials Consortium. Pts with mCRPC are randomized (1:1) to docetaxel or docetaxel + Ra-223. Pts with ≥2 bone lesions and progression by Prostate Cancer Working Group 3 criteria are eligible. Other key inclusion criteria are an Eastern Cooperative Oncology Group performance status of 0–1 and normal organ function. Key exclusion criteria are: use of anticancer therapy ≤4 weeks (wks) before randomization and use of bone-seeking radiopharmaceuticals or chemotherapy in the castration-resistant setting, and bulky visceral metastases (≥3 lung and/or liver or a lesion ≥2 cm in the previous 8 wks). Pts will receive docetaxel 75 mg/m² IV q3w for 10 doses with oral prednisone 5 mg b.i.d. or docetaxel 60 mg/m² IV q3w for 10 doses with oral prednisone 5 mg b.i.d. + Ra-223 55 kBq/kg IV q6w for 6 injections. The primary endpoint is overall survival. Secondary and exploratory endpoints include: radiographic progression-free survival, symptomatic skeletal event-free survival, safety, markers of bone metabolism, alterations in circulating tumor cells and DNA, detection of androgen-receptor splice variant 7 and changes in automated bone scan index. Enrollment of 738 pts is expected. The study is conducted in the US and Netherlands. Clinical trial information: NCT03574571