AR gene mutations in the LBD that alter ligand specificity and/or functional activity exist and are thought to contribute to the conversion of some AR antagonists into agonists, which explains the paradoxical temporary improvement sometimes observed in patients when antiandrogen therapy is stopped. These mutations can have great effect on the antagonist activities of current small molecule antiandrogens and make them less efficient in blocking AR function via indirect modulation from inside of the LBP. Recent studies with circulating tumor cells, suggest that the mutation frequency is higher than previously assumed based on tumor biopsies.
The T877A, W741L and W741C mutations  are examples of known AR LBD mutations. The LNCaP prostate cancer cell line expresses AR with a T877A point mutation that causes proliferation in the presence of the antiandrogens hydroxyflutamide and cyproterone acetate. This mutation has also been discovered in patients with antiandrogen withdrawal syndrome being treated with these compounds. In another study, bicalutamide treatment of LNCaP cells resulted in two LBD mutations, W741L and W741C, causing bicalutamide to acquire agonist activity to both mutant ARs. The W741L mutation generates additional space such that the sulfonyl-linked phenyl ring of bicalutamide is accommodated at the location of the missing indole ring of W741. In non-mutant AR, the presence of the W741 side chain probably forces bicalutamide to protrude out thus precluding the active position of H12 on the AR receptor.
However, hydroxyflutamide worked as an antagonist for W741 mutant ARs. This concurs with the theory that flutamide and nilutamide antagonize AR through the mechanism of “passive antagonism”, as they are of a more modest size then bicalutamide. These drugs may therefore be effective as a second-line therapy for refractory prostate cancer previously treated with bicalutamide.