A randomized phase II study comparing cabazitaxel/prednisone to cabazitaxel alone for second-line chemotherapy in men with metastatic castrate resistant prostate cancer (mCRPC): CABACARE

Abstract

Background: In theTROPIC study, cabazitaxel (CAB), administered with prednisone (PDN) 10 mg daily, showed significant advantage in OS and PFS in patients (pts) progressing during or after docetaxel (DOC) treatment. Similar to DOC, CAB has been approved in combination with daily PDN, although the contributing role of PDN to efficacy and safety has been poorly investigated. Corticosteroids have a variety of effects, which may be either favourable, mediated by adrenal androgen and cytokine suppression, or detrimental, because of adverse events associated with long‐term use, promiscuous activation of AR, immunosuppression, activation of AR variants highly sensitive to PDN even at low concentrations. Moreover PDN acts as a CYP3A4 inducer, affecting clearance of taxanes. It has been shown that AR point mutations are rare in therapynaive pts but occur in 15‐45% of CRPC pts and can increase AR affinity for a wide range of steroids. Over 100 mutations have been described. In the CHAARTED trial DOC was safely administered without daily PDN showing important clinical benefits in OS, PFS, and time to CRPC.; Safety data for CAB without PDN are lacking. AR‐V7 positivity and RB loss/inactivation have been identified as potentially implicated in progression with next‐generation targeted agents. We also would like to prospectively assess their role as predictive biomarkers of CAB activity. Trial design: CABACARE is a randomized, phase II, open label, multicenter study comparing CAB at 25 mg/m2 q21 plus daily PDN (10 mg) vs CAB at 25 mg/m2 q21 alone in mCRPC pts progressed during or after DOC treatment. The study is designed to test non‐inferiority in terms of PFS, according to PCWG‐2, of CAB alone vs CAB plus PDN, assuming that the two arms are equally effective. Each arm will enroll 110 pts. Main secondary objectives are: safety, QoL, pain assessment, overall response rate (ORR), PSA response, time to PSA progression, time to radiological progression; OS; and time to skeletal related events (SRE). The influence of Arv7 and RB status on CAB activity will also be evaluated.