9523 Background: Treatment with BRAF+/-MEK inhibition (BRAF+/-MEKi) has revolutionized treatment in melanoma and other cancers, but resistance is common and innovative treatment strategies are needed. Sexual dimorphism in response to BRAF+/-MEKi have been noted, but mechanisms behind this are poorly understood and hormonal modulation has not been well-studied in this setting. Methods: We examined outcomes by sex in five clinical cohorts of patients (pts) (total n = 792, 362 female, 430 male) with BRAF-mutated melanoma who were treated with BRAF/MEKi in either the neoadjuvant or metastatic setting. Rates of major pathologic response (MPR), clinical benefit (CB), progression free survival (PFS) relapse-free survival (RFS) and overall survival (OS) were assessed. Translational research studies were performed on available pre- and on-treatment tumor samples (n = 27 pts) including RNA sequencing and profiling androgen receptor (AR) expression. Parallel studies were performed in preclinical models to assess the effect of sex and AR modulation on response to BRAF+/-MEKi. Results: In this study, improved rates of MPR, CB, PFS and OS were observed in female vs male pts. Specifically, female patients treated with neoadjuvant BRAF+MEKi showed significantly higher rates of MPR (66% v. 14%, p = 0.001), and improved RFS (64% versus 32% at 2 years, p = 0.021) vs male pts in the neoadjuvant setting (n = 51). These findings were not observed in a 2^nd smaller trial of pts (n = 35), but were validated in a cohort of pts with unresectable metastatic melanoma treated with BRAF+MEKi (n = 69), with significantly higher rates of CB (80% v. 68%, p = 0.022) and PFS (12 v. 7 months, p = 0.003) in female vs male pts. Data from several published trials was analyzed (COMBI-D and METRIC trials), demonstrating improved PFS/OS at 2 years in female vs male pts treated with combined BRAF/MEKi (n = 211; p = 0.03 and, p = 0.04) and in female vs male pts treated with MEKi monotherapy (n = 206; p = 0.04 and p = 0.002), but not in female vs male pts treated with BRAFi monotherapy (n = 211; p = 0.21 and 0.095). Significantly higher expression AR expression was observed in available on- vs pre-treatment samples from male pts (p = 0.01), suggesting that treatment with BRAF/MEKi may induce AR expression in tumors. Findings were recapitulated in several preclinical models, and treatment with pharmacologic inhibitors of AR signaling (enzalutamide) in combination with BRAF/MEKi was associated with significantly enhanced anti-tumor activity in both male and female mice (p = 0.003 and p < 0.0001). Conversely, systemic treatment with testosterone was associated with significantly impaired tumor control in male and female mice (p = 0.021 and < 0.001). Conclusions: These data suggest that AR blockade may promote BRAF/MEKi response in melanoma, warranting further investigation in clinical trials. The impact of AR signaling, and modulation should be studied in MAPK-targeted therapy across other cancer types.