Background: Cabozantinib (C) is a multikinase inhibitor of c-Met, vascular endothelial growth factor receptor two and RET. C has shown activity in metastatic castrate resistant prostate cancer (mCRPC), with resolution of bone lesions on bone scan (BS), regression of soft tissue/visceral disease (STD), reductions in circulating tumor cells and bone biomarkers. Combining docetaxel (D) with other agents, without overlapping toxicities, can target different cellular signaling pathways necessary for tumor survival. Methods: Patients (pts), with no prior D for CRPC, receive a fixed dose of D (75 mg/m2 IV day one of each 21 day cycle) and prednisone (P) (5 mg po q12 hours) with C at three escalating dose levels: 20 mg, 40 mg, or 60 mg (all po daily). Using a standard three-plus-three design, three to six pts are treated at each dose level until the maximum tolerated dose (MTD) has been defined. Results: Thirteen pts have been accrued; four on dose level one, six on dose level two, and three on dose level three. Median age 69 (45 to 84). Four pts have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of zero and nine pts have a PS of one. Median Gleason score is nine (7 to 10). Median on-study prostate-specific antigen (PSA) is 129.2 ng/mL (0.01-508.5 ng/mL). Median cycles is six (1 to 17). Grade 1 adverse events (AEs), possibly related to C; dysgeusia (4/12), oral mucositis (4/12), increased ALT (3/12), and epistaxis (3/12). Grade 2 AEs; nausea (2/12), hand/foot syndrome (2/12), fatigue (2/12), dysgeusia (2/12), oral mucositis (2/12), hypophosphatemia (2/12), and anemia (2/12). Grade 3 AE is hypophosphatemia (2/12). Grade 4 AE is neutropenia (1/12). MTD of C is 60 mg. Of nine evaluable pts, six have bone only disease. Of these six, three pts have PSA declines of less than 30% with improvement on BS (two pts) or stable BS (one pt). The other three pts have PSA declines of greater than 30% and bone scan improvement. Three pts have STD and bone disease; one patient had a PSA decline of greater than 30% with improvement on BS and SD by CT scan. One patient had an increase in PSA of less than 30% with improvement on BS and CT. The third pt had PD by CT and an increase in PSA equal to 30%. PFS probability at six months is 90.0% and is 67.5% at eight months and beyond. Conclusions: The addition of C to D and P, has an acceptable toxicity profile. CT scan and BS improvements did not correlate with PSA declines in all pts. An expansion cohort will combine D plus P with C at the MTD (60 mg) to determine clinical benefit. Clinical trial information: NCT01683994.