Second generation anti-androgen agents in prostate cancer treatment

Second generation antiandrogens have two major mechanisms to overcome the limitations of first generation antiandrogens in the management of prostate cancer. 

1-Abireratone acetate is a pregnenolone analog that effectively inhibits 17 alpha hydroxylase, a CYP 17 A1-mediated androgen synthesis in testicular, prostate, and adrenal tissues.

2-Direct androgen receptor inhibitors: enzalutamide, darolutamide, and apalutamide exhibit increase specificity and potency by blocking androgen receptor activity.

These agents have demonstrated survival benefit beyond androgen deprivation therapy alone in randomized clinical trials. 

They had dramatically changed the landscape of prostate cancer treatment.

These androgen receptor inhibitors act by competitively inhibiting antigen binding, antigen receptor nuclear translocation, and androgen receptor mediated transcription.

These androgen receptor inhibitors approved for nonmetastatic call prostate cancer improve metastasis free survival an overall survival and appear to have similar efficacy.

These androgen receptor inhibitors prolong metastatic free survival by approximately two years.

Adding androgen receptor pathway inhibitors such as apalutamide, enzalutamide, abiraterone and darolutamide , the median time to castration resistance has not been reached in most studies and proximately 60% of patients continue to respond to treatment after a follow up of four years.

Enzalutamide and apalutamide are similar drugs, essentially analogues of each other.

Enzalutamide and apalutamide significantly increase the risk of fractures and falls, as well as dizziness and cognitive impairment.

Darolutamide does not readily into the blood brain barrier, and does not have any significant mental or memory impairment associated with it.

Darolutamide is not associated with an increased incidence of falls or fracture.

Darolutamide does not significantly increase rates of CNS toxicities cities, including mental and memory impairment,

Darolutamide Is administered twice daily, while enzalutamide and apalutamide are administered daily.

The three second generation androgen receptor inhibitorsare well tolerated: Apalutamide is associated with rash and both enzalutamide and apalutamide can predispose to seizures.

Enzalutamide and apalutamide have drug interactions, particularly with anticoagulants.

Daralutamide can increase the serum concentration of statins.

The overall survival is much greater with the use of second generations AR inhibitors with non-metastatic disease.

In a systemic systematic review and meta-analysis of 12 randomized clinical trials comprising 13,524 patients there was an increased risk of cognitive toxic effects, fatigue, and falls among individuals treated with second generation anti-androgens for prostate cancer (Nowakowska ML).


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