Efficacy of novel BET inhibitors in combination chemotherapy for castrationresistant prostate cancer

VÁZQUEZ, RAMIRO; CIVENNI, GIANLUCA; SHINCE, DHEERAJ; CANTERGIANI, JASMINE; MARCHETTI, MARTINA; ZOPPI, GIADA; KOKANOVIC, ALEKSANDRA; MERULLA, JESSICA; ALBINO, DOMENICO; RUGGERI, BRUCE; LIU, PHILLIP; CARBONE, GIUSEPPINA M.; CATAPANO, CARLO V.

European Urology Oncology

ELSEVIER

Lugar: Ámsterdam; Año: 2021

2588-9311

Background: Chemotherapy is the treatment of choice for metastatic castration-resistant prostate cancer (CRPC) non-responsive to androgen receptor-targeted therapies. Nevertheless, the impact of chemotherapy on patient survival is limited and clinical outcome remain dismal. Bromodomain and extra-terminal inhibitors (BETi) are attractive therapeutic agents and are currently in clinical trials to test their efficacy in prostate cancer patients.Objective: In this study, we evaluated the activity of two clinical stage BETi, INCB054329and INCB057643, alone and in combination with chemotherapeutics used for treatment of mCRPC.Design, setting and participants: Drug activity was evaluated in vitro by MTT, clonogenic and prostato-sphere assays. The in vivo activity was evaluated in mice bearing 22Rv1 tumor xenografts.Outcome measurements and statistical analysis: Cell growth data were analyzed to determine Emax and EC50. For concomitant treatments, the combination index was determined according to the Chou-Talalay method. For in vivo activity, changes in tumor size (T/Ci%), weight (T/Cd%), doubling time (DT) and mouse body weight were monitored. Statistical significance was determined by one-way ANOVA 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 androgen-independent 22Rv1 xenografts. Combined treatment with INCB057643 and either docetaxel, carboplatin or olaparib was synergistic/additive in vitro. Notably, INCB057643, given with a low-intensity dosing schedule, greatly enhanced the antitumor activity of docetaxel, carboplatin and olaparib in 22Rv1 tumor xenografts.Conclusions: Collectively, these results provide the first evidence of the therapeutic benefits obtainable by combining BETi with non-androgen receptor targeted therapies for treatment of mCRPC.Patient summary: Chemotherapy has limited efficacy in patients with mCRPC. This studyprovides evidence of enhanced efficacy of clinically used chemotherapeutics when given incombination with the BETi INCB057643, expanding the horizon of the current options fortreatment of prostate cancer.