Enhanced Antitumor Efficacy of Radium-223 and Enzalutamide in the Intratibial LNCaP Prostate Cancer Model

: Suominen MI, Knuuttila M, Schatz CA, Schlicker A, Vaaraniemi J, Sjoholm B, Alhoniemi E, Haendler B, Mumberg D, Kakonen SM, Scholz A

Publisher: MDPI

: 2023

: International Journal of Molecular Sciences

: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

: INT J MOL SCI

: 2189

: 24

: 3

: 15

DOI: https://doi.org/10.3390/ijms24032189

Radium-223 dichloride and enzalutamide are indicated for metastatic castration-resistant prostate cancer and their combination is currently being investigated in a large phase 3 clinical trial. Here, we evaluated the antitumor efficacy of radium-223, enzalutamide, and their combination in the intratibial LNCaP model mimicking prostate cancer metastasized to bone. In vitro experiments revealed that the combination of radium-223 and enzalutamide inhibited LNCaP cell proliferation and showed synergistic efficacy. The combination of radium-223 and enzalutamide also demonstrated enhanced in vivo antitumor efficacy, as determined by measuring serum PSA levels in the intratibial LNCaP model. A decreasing trend in the total area of tumor-induced abnormal bone was associated with the combination treatment. The serum levels of the bone formation marker PINP and the bone resorption marker CTX-I were lowest in the combination treatment group and markedly decreased compared with vehicle group. Concurrent administration of enzalutamide did not impair radium-223 uptake in tumor-bearing bone or the ability of radium-223 to inhibit tumor-induced abnormal bone formation. In conclusion, combination treatment with radium-223 and enzalutamide demonstrated enhanced antitumor efficacy without compromising the integrity of healthy bone. The results support the ongoing phase 3 trial of this combination.