Antiandrogens & 5α-Reductase Inhibitors

5α-reductase inhibitors. The enzyme 5α-reductase converts testosterone to the more potent androgen DHT, which drives development and enlargement of the prostate. Finasteride inhibits the type II enzyme; dutasteride inhibits both type 1 and type 2. Both treat symptomatic benign prostatic hyperplasia in men with an enlarged prostate — improving symptoms and reducing the risk of acute urinary retention and surgery — alone or with an alpha-blocker (finasteride with doxazosin; dutasteride with tamsulosin, also sold combined as Jalyn). Propecia (finasteride) treats male pattern hair loss in men only.

Androgen receptor inhibitors. Flutamide, bicalutamide and nilutamide block androgen action at the receptor and are used with medical or surgical castration in prostate cancer. Enzalutamide, apalutamide and darolutamide also block androgen binding and then nuclear translocation of the receptor and its interaction with DNA; patients also receive a GnRH analog or have had bilateral orchiectomy (enzalutamide for high-risk biochemical recurrence may be used with or without one). Abiraterone blocks androgen synthesis instead, by inhibiting CYP17 in the testes, adrenal glands and prostate tumor tissue.

These drugs lower serum PSA by about 50%, even when prostate cancer is present. A new PSA baseline is set after several months of treatment; any confirmed rise from the lowest value may signal prostate cancer and is evaluated, even if it is still in the normal range. They may increase the risk of high-grade prostate cancer, and other urological conditions — including prostate cancer, which can coexist with BPH — are considered before starting.

Because DHT is needed for normal development of male genitalia, these drugs may cause abnormal external genitalia in a male fetus. They are contraindicated in pregnancy, and women who are or may be pregnant must not handle crushed or broken finasteride tablets or leaking dutasteride capsules — dutasteride is absorbed through the skin. Men on dutasteride wait at least 6 months after the last dose before donating blood, so a pregnant transfusion recipient is not exposed.

Flutamide has a boxed warning for hepatic injury, including liver failure and death, and nilutamide a boxed warning for interstitial pneumonitis; nilutamide and bicalutamide also carry hepatitis warnings. Transaminases are checked before starting, regularly through the first 4 months and periodically after, and the drug is stopped for jaundice or an ALT above twice the upper limit of normal. Bicalutamide and flutamide raise the prothrombin time in patients on warfarin.

With enzalutamide, seizures occur (more often with predisposing factors) and the drug is stopped permanently if one occurs; PRES, falls and fractures, and ischemic heart disease are also warnings. Apalutamide carries warnings for cerebrovascular and ischemic cardiovascular events, fractures, falls, seizure, severe skin reactions and interstitial lung disease; darolutamide for ischemic heart disease and seizure. Enzalutamide and apalutamide are strong CYP3A4 inducers that lower levels of many other drugs.

Blocking CYP17 can raise adrenal mineralocorticoid production, causing hypertension, hypokalemia and fluid retention. Zytiga is labeled with prednisone and Yonsa with methylprednisolone; blood pressure is controlled and hypokalemia corrected before treatment, and blood pressure, potassium and fluid retention are checked at least monthly. QT prolongation and torsades de pointes have occurred in patients who developed hypokalemia.

Adrenocortical insufficiency can follow interruption of the corticosteroid, infection or stress, and higher corticosteroid doses may be needed around stressful situations. Abiraterone can cause severe, even fatal hepatotoxicity, so transaminases and bilirubin are checked before and frequently during treatment. Zytiga is taken on an empty stomach because food raises exposure; Yonsa has different dosing and food effects, so the products are not substituted for each other.