Abstract 6324: Intercepting bladder cancer progression using androgen receptor inhibitor, apalutamide, in a carcinogen BBN-induced rat bladder tumor model

Abstract Bladder cancer (BC) is the 2nd most commonly diagnosed genitourinary cancer. While the majority of cancers are diagnosed and treated at the non-muscle invasive stage; high recurrence rate, treatment resistance, and tumor progression cause significant mortality. Epidemiologic and preclinical data have long demonstrated clear differences in incidence and progression of BC between genders, suggesting strong association with hormonal pathways with development and progression in these tumors. Based on these studies, androgen receptor (AR) signaling pathway emerged as a critical player and a promising target for BC interception. Thus, in the current study, BC preventive efficacy of the nonsteroidal AR antagonist, apalutamide, was evaluated in a N-butyl-N-(4-hydroxyl)-nitrosamine (BBN)-rat BC model. At 7 weeks of age, fisher rats were randomized by weight into 4 groups (30 rats/group/gender: 24 BBN + 6 Vehicle). Starting at 8 weeks of age, rats were administered BBN by oral gavage (150mg/dose; twice weekly for 8 weeks) to induce BC. A week after BBN treatment, rats in each group received apalutamide by oral gavage (5 days/wk) at increasing doses, 0, 7.5, 15, or 30mg/kg BW, until termination. Male and female bladder tumors were assessed at 40 & 50 weeks of age, respectively. Body and organ weights, blood profile, liver and kidney enzyme function analysis suggested non-significant differences, indicating safety of the tested doses. BBN treatment induced bladder tumors in both genders, resulting in significantly larger bladders (∼0.75±0.25g) compared to vehicle group (0.12±0.08g) with the incidence of large tumors (≥200mg) in 87% and 75% of male and female rats, respectively. Importantly, apalutamide treatment led to a significant reduction of bladder weights suggesting tumor growth inhibition in treated rats compared to control. Bladder weights were reduced by 60%-65% in males (p<0.05) and by 54%-63% in females (p<0.05) when compared to the untreated group. Moreover, the incidence of large bladder tumors was also significantly decreased with apalutamide 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. Histopathological analysis of the tumor demonstrated a significant decrease in papillomas (40%-60% less vs control; p<0.01-p<0.0001), NMIBC (48%-76% less vs control; p<0.001-p<0.0001) and MIBC (>77% less vs control; p<0.001-p<0.0001) at all three doses tested. Biomarker analysis showed reduction in the proliferation markers Ki67 and cyclin D1 in apalutamide treated rats tumors. In conclusion, our study demonstrated that an AR antagonist, apalutamide, can intercept bladder tumor growth and progression in a preclinical rat model and warrants further investigation in clinical trials. (Project funded 100% with Federal funds from NCI, NIH, DHHS, under Contract 75N91019D00020_75N91022F00002) Citation Format: Venkateshwar Madka, Gopal Pathuri, Surya Pratap Singh, Anil Singh, Anh Bao, Nicole Stratton, Shizuko Sei, John L. Clifford, Chinthalapally V. Rao. Intercepting bladder cancer progression using androgen receptor inhibitor, apalutamide, in a carcinogen BBN-induced rat bladder tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6324.