Pharmaceutical Intermediate
Enzalutamide and Apalutamide Dec 13 , 2021

Second Generation Antiandrogens


Enzalutamide was first described in 2009 as a second-generation antiandrogen with higher affinity for the AR than 

bicalutamide, and capable of retaining activity in the presence of increased AR expression, often seen in metastatic PCa. 

Enzalutamide also prevented nuclear translocation of the AR and impaired binding of the AR DNA binding domain to 

hormone response elements in androgen responsive genes (McEwan, 2013). Since its identification, enzalutamide has entered

the clinic for therapeutic use in several developed countries. Despite its increased efficacy compared to bicalutamide,

research has still unveiled mechanisms of resistance in patients, including an inactivating F868L mutation inthe AR LBD

(Lallous et al., 2016). Resistance is also conferred by the expression of AR splice variants lacking the LBD(Antonarakis et al., 2014).

A long, non-coding RNA Malat1 has also been shown to drive enzalutamatide mediated selection of AR-v7 expression and 

downregulation of this splice variants can be achieved by siRNA and the degradation  enhancer ASC-J9 (Wang et al., 2017).


The F868L mutation has also been shown to confer resistance to apalutamide (ARN-509, Table 2) which is currently in phase III

clinical trials for castrate-resistant prostate cancer (Balbas et al., 2013). Although apalutamide was reported to have greater

efficacy than enzalutamide in animal models of PCa, alongside absence of AR nuclear localisation or DNA binding, it remains to

be seen how the drug will compare to enzalutamide in a large-scale trial.

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