Efficacy of Novel Bromodomain and Extraterminal Inhibitors in Combination with Chemotherapy for Castration-Resistant Prostate Cancer

Abstract

Background: Chemotherapy is the treatment of choice for metastatic castration-resistant prostate cancer (mCRPC) nonresponsive to androgen receptor-targeted therapies. Nevertheless, the impact of chemotherapy on patient survival is limited and clinical outcome remain dismal. Bromodomain and extraterminal inhibitors (BETis) are attractive therapeutic agents and currently in clinical trials to be tested for their efficacy in prostate cancer patients.

Objective: In this study, we evaluated the activity of two clinical stage BETis, INCB054329 and INCB057643, alone and in combination with chemotherapeutics used for the treatment of mCRPC.

Design, setting, and participants: Drug activity was evaluated in vitro by MTT, clonogenic, prostato-sphere, and flow cytometry assays. The activity in vivo was evaluated in mice bearing prostate tumor (22Rv1) xenografts.

Outcome measurements and statistical analysis: Cell growth data were analyzed to determine the maximum effect and the concentration that reduces by 50%. For concomitant treatments, the combination index was determined according to the Chou-Talalay method. For in vivo activity, changes in tumor size (T/C_i%), weight (T/C_d%), doubling time, and mouse body weight were monitored. Statistical significance was determined by one-way analysis of variance followed by a Student-Newman-Keuls or Turkey a posteriori test.

Results and limitations: INCB054329 and INCB057643 had significant activity as single agents in human prostate cancer cell lines and 22Rv1 tumor xenografts. Combined treatment with INCB057643 and any of docetaxel, olaparib, or carboplatin was synergistic/additive in vitro. Notably, INCB057643, given with a low-intensity dosing schedule, greatly enhanced the anti-tumor activity of docetaxel, carboplatin, and olaparib in 22Rv1 tumor xenografts.

Conclusions: Collectively, these results provide the first evidence of the therapeutic benefit obtainable by combining BETis with non-androgen receptor-targeted therapies for the treatment of mCRPC.

Patient summary: Chemotherapy has limited efficacy in patients with metastatic castration-resistant prostate cancer. This study provides evidence of enhanced efficacy of clinically used chemotherapeutics when given in combination with the bromodomain and extraterminal inhibitor INCB057643, expanding the horizon of the current options for the treatment of prostate cancer.

Keywords: Bromodomain inhibitors; Carboplatin; Castration-resistant prostate cancer; Docetaxel; INCB054329; INCB057643; Olaparib; Prostate cancer.