Efficacy of androgen receptor inhibitor, Apalutamide, in intercepting bladder cancer in a BBN-induced rat bladder tumor model

Bladder cancer (BC) is the second-most diagnosed genitourinary cancer. Most tumors are detected at the non-muscle invasive (NMIBC) stage and treated; however high recurrence rate, treatment resistance, tumor progression and metastasis contribute to significant mortality annually. Many studies have indicated significantly higher incidence rates and BC progression to be more predominant in men. Experimental data have also showed strong association of BC tumorigenesis with androgen receptor (AR) signaling , making AR a promising target for cancer interception. In this study, AR antagonist, apalutamide (APA) was evaluated for BC preventive efficacy in a N-butyl-N-(4-hydroxyl)-nitrosamine (BBN)-rat BC model. Male and female Fischer rats were randomized into placebo and intervention groups (30 rats/group/sex: 24 BBN+6 Saline). At 8 weeks of age, rats in carcinogen groups received BBN by oral gavage (150mg/dose; 2x/week for 8 weeks) to induce BC. APA was given to rats in intervention groups at 7.5, 15, or 30mg/kg body weight by oral gavage (5x/week) until termination. Early intervention with APA started at carcinogenesis stage i.e., a week after last BBN, while delayed intervention began at papilloma stage i.e., ~10 weeks after last BBN. Bladder tumors were assessed at 40 and 50 weeks of age in male and female rats respectively. APA did not cause any overt-toxicities. BBN treatment induced bladder tumors in all rats, resulting in significantly larger bladders in placebo group compared to normal bladders in saline group. Importantly, APA significantly reduced bladder weights suggesting tumor growth inhibition in intervention groups compared to placebo. With early intervention, bladder weights were reduced by 60%-65% in male rats (p<0.05) and by 54%-63% in female rats (p<0.05) when compared to the placebo group. Incidence of large bladder tumors was also significantly decreased with APA treatment by 30%-47% in males (p<0.05-p<0.01) and by 32%-50% in females (p<0.05) in a dose dependent manner. Delayed intervention also resulted in 21%-53% (p<0.01) reduction of bladder weights and 28%-66% less incidence of large tumors in male rats only. Histopathological analysis of the tumor sections demonstrated suppression of tumor progression in APA treated rats as indicated by the significant decrease in multiplicity of papillomas, NMIBC, and MIBC when compared to placebo. Biomarker and gene expression analysis suggested modulation of critical tumor promoting pathways with APA treatment. In summary, this preclinical study demonstrated that an AR antagonist, apalutamide, can intercept bladder tumor growth and progression and warrants further investigation in clinical trials. (Project funded in whole with Federal funds from the NCI-NIH, DHHS, under Contract No. 75N91019D00020 - 75N91022F00002).