Background: Retinoblastoma (RB) loss of function has been identified as a process by which castration-resistant tumors develop. Up to 60% of CRPC tumors show loss of RB function. This can drive the transition to castration resistance in human xenograft models. The androgen receptor (AR) appears to be under stringent RB control; RB loss results in AR deregulation and bypass of androgen deprivation therapy. Tumors lacking RB are compromised for DNA damage checkpoints that allow for repair after genomic insult. Thus,tumors devoid of RB function are hypersensitive to chemotherapy. These findings support the hypothesis that RB status can guide treatment with specific chemotherapies and improve disease outcome. RB status may be a potential biomarker for pts who fail AR-directed drugs such as abiraterone (AA). While docetaxel is the standard first line chemotherapy for mCRPC, cabazitaxel (CBZ) is a more potent microtubule inhibitor. This trial will determine the effect of AA followed by CBZ upon disease progression versus an upfront combination of AA and CBZ in pts with chemotherapy naïve mCRPC. RB status at baseline and the feasibility of obtaining RB status from circulating tumor cells (CTCs) were examined. Methods: Chemotherapy naïve mCRPC pts received AA 1000 mg po daily + prednisone 5 mg po BID either in combination with CBZ 25 mg/m2 IV q 3 weeks (up to 9 cycles) or followed by CBZ upon progression. The primary endpoint was radiographic progression free survival with a planned accrual of 80 pts. Correlatives included baseline tumor biopsies, RB status based on immunohistochemistry and gene signature, CTCs using the EPIC Sciences platform, and serial androgen levels. EPIC Sciences established the N-terminal expression cut-off using spiked healthy donor blood with PC3 and LnCaP cells. FISH analyses to assess RB loss were defined as: Non-Deleted: RB = copy control, RB deletion: RB < copy control; 13q deletion: RB and copy control both < 2. CTCs were non-evaluable and not included in FISH analysis if: < 4 CTCs/slide, Apoptotic CTCs, low signal and/or loss of CTC during processing. Twenty-four pts are enrolled to date. Supported by Sanofi-Aventis, PCF Clinical trial information: NCT02218606