Background: Docetaxel (D) is standard first-line chemotherapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Cabazitaxel (C), a novel taxane developed to overcome D resistance, showed an overall survival improvement in second line CRPC in a three-weekly dose schedule. Its main toxicity is hematological, especially in unfit patients. We aimed to evaluate efficacy and safety of weekly C/pred. in "unfit" mCRPC previously treated with D. Methods: Unfit pts (ECOG 2, dose reduction due to febrile neutropenia during treatment with D or radiation therapy affecting more than 25% of bone marrow reserve) with advanced CRPC progressing after D treatment with ECOG <=2 and adequate bone marrow, liver and kidney functions were included. C 10 mg/m2 was administered on days 1, 8, 15, and 22 of 5-week cycles with daily pred. 5 mg b.i.d. Radiological and prostate-specific antigen response was evaluated according to the PCCTWG II criteria and toxicity according NCI-CTC AE. Results: To date 47 pts have been enrolled and data are available for 38. Median age was 72 (range 56 to 83), 20 (53%) pts had ECOG 2, 29 (83%) had bone metastases. Cycles administered: 124 (median: 3; range: 1 to 9) and 446 weekly administrations (median 11; range 1 to 35). Mean dose intensity was 94%. Most frequent toxicities of all grades as % of cycles were: asthenia (20%), anemia (50%), leukopenia (13%), thrombocytopenia (14%), diarrhea (9%), rash (6%), nauseas (5%), dysgeusia (7%), xerostomia (6%), anorexia (5%), hand-foot syndrome (5%), and neuropathy (2%). Grade 3: thrombocytopenia (10%), anemia (6%), neutropenia (1%), asthenia (3%), anorexia (1%), mucositis (1%), nausea (1%), and vomiting (1%). No grade 4 toxicities were reported. Three patients discontinued the study due to asthenia G3 (2) and mucositis G3 (1). No grade III/IV diarrhea or febrile neutropenia were observed. Conclusions: Administration of weekly C (10 mg/m2) to unfit pts seems to be safe with no grade 3 or greater neutropenia, diarrhea, or febrile neutropenia reported. If activity is confirmed, weekly C may represent an attractive option for unfit pts with mCRPC progressing after D treatment. Clinical trial information: NCT01518283.