Mechanism of Action of Nonsteroidal Anti-Androgens. The nonsteroidal anti-androgens are taken orally and inhibit ligand binding and consequent AR translocation from the cytoplasm to the nucleus.
Flutamide. Flutamide has a t1/2 of 5 hours and therefore is given as a 250-mg dose every 8 hours. Its major metabolite, hydroxyflutamide, is biologically active; there are at least five other minor metabolites (Luo et al., 1997). The common side effects include diarrhea, breast tenderness, and nipple tenderness. Less commonly, nausea, vomiting, and hepatotoxicity occur (Wysowski and Fourcroy, 1996; Wysowski et al., 1993).
Bicalutamide. Bicalutamide (casodex, others) has a serum t1/2 of 5-6 days and is taken once daily at a dosage of 50 mg/day when given with a GnRH agonist. Both enantiomers of bicalutamide undergo glucuronidation to inactive metabolites, and the parent compounds and metabolites are eliminated in bile and urine. The elimination t1/2 of bicalutamide is increased in severe hepatic insufficiency and is unchanged in renal insufficiency.
Bicalutamide is well tolerated at higher doses with rare additional side effects. Daily bicalutamide (either low or high dose) is significantly inferior compared with surgical or medical castration (Bales and Chodak, 1996; Tyrrell et al., 1998). Although the ease of administration and favorable toxicity are attractive, concerns about inferior survival has limited the use of bicalutamide monotherapy.
Nilutamide. Nilutamide (niladron) is a second-generation anti-androgen with an elimination t1/2 of 45 hours, allowing once-daily administration at 150 mg/day. Common side effects include mild nausea, alcohol intolerance (5-20%), and diminished ocular adaptation to darkness (25-40%); rarely, interstitial pneumonitis occurs (Decensi et al., 1991; Pfitzenmeyer et al., 1992). It is metabolized to five known products that are all excreted in the urine. Nilutamide appears to offer no benefit over the first-generation drugs above and has the least favorable toxicity profile (Dole and Holdsworth, 1997).
Estrogens. High estrogen levels can reduce testosterone to castrate levels in 1-2 weeks via negative feedback on the hypothalamic– pituitary axis. Estrogen also may compete with androgens for steroid hormone receptors and may thereby exert a cytotoxic effect on prostate cancer cells (Landström et al., 1994). Numerous estrogenic compounds have been tested in prostate cancer. Estrogens are associated with increased myocardial infarctions, strokes, and pulmonary emboli and increased mortality, as well as impotence, loss of libido, and lethargy. One benefit is that estrogens prevent bone loss (Scherr et al., 2002).
Most early studies on the use of estrogens used DES and were conducted between 1960 and 1975 by the Veterans Administration Cooperative Urological Research Group (VACURG). Two studies compared orchiectomy to different doses of DES to placebo (Byar, 1973; Byar and Corle, 1988). DES was as effective as orchiectomy for metastatic prostate cancer but was associated with an increase in cardiovascular events, including myocardial infarction, cerebrovascular accident, and pulmonary embolism (Bailar and Byar, 1970; Byar, 1973; de Voogt et al., 1986; Waymont et al., 1992). Due to its cardiovascular toxicity and unacceptable mortality at any dose level, DES is not indicated for prostate cancer treatment and is not available in North America for that purpose. Other synthetic estrogens have a similar associated cardiovascular toxicity to that of DES but without the efficacy. These compounds include conjugated estrogens (premarin, others), ethinyl estradiol, medroxyprogesterone acetate (provera, others), and chlorotrianisene (no longer marketed in the U.S.).
Inhibitors of Steroidogenesis. In the castrate state, AR signaling, despite low steroid levels, supports continued prostate cancer growth. AR signaling may occur due to androgens produced from nongonadal sources, AR gene mutations, or AR gene amplification. Nongonadal sources of androgens include the adrenal glands and the prostate cancer cells themselves (Figure 63–4). Androstenedione, produced by the adrenal glands, is converted to testosterone in peripheral tissues and tumors (Stanbrough et al., 2006). Intratumoral de novo androgen synthesis also may provide sufficient androgen for AR-driven cell proliferation (Montgomery et al., 2008).
Ketoconazole is an antifungal agent that interrupts the synthesis of an essential fungal membrane sterol. In an unrelated action, ketoconazole inhibits both testicular and adrenal steroidogenesis by blocking CYPs, primarily CYP17 (17α-hydroxylase). Ketoconazole is administered off label as secondary hormone therapy to reduce adrenal androgen synthesis in castration-resistant prostate cancer (Small et al., 2004). Ketoconazole causes significant diarrhea and hepatic enzyme elevations that limit its use as initial hormone therapy. Consequent poor patient adherence deters from its efficacy. Ketoconazole is given in doses of 200 mg or 400 mg three times daily. Hydrocortisone supplementation is co-administered to compensate for inhibition of adrenal steroidogenesis at the 400-mg dose level. A related compound, itraconazole, inhibits the activation of Smoothened (SMO), a component of the Hedgehog (Hh) signaling pathway (Kim et al., 2010), which is overly active in certain cancers. Thus, this class of antifungal agents may act by several distinct mechanisms and prove useful in treating other cancers.
Abiraterone is an irreversible inhibitor of both 17α-hydroxylase and C-17,20-lyase CYP17 activity, with greater potency and selectivity compared with ketoconazole. The parent compound, abiraterone acetate, is orally bioavailable and has been well tolerated in castration-resistant prostate cancer patients as secondary hormone therapy in phase I and II studies (Attard et al., 2009; Attard et al., 2008). With continuous administration, abiraterone increases ACTH levels, resulting in mineralocorticoid excess. Therefore, abiraterone acetate is administered with daily low-dose glucocorticoids, such as prednisone. Ongoing phase III trials will evaluate the efficacy and appropriate timing of abiraterone therapy for prostate cancer patients.