Hormonal Therapy for Prostate Cancer

Abstract

Huggins and Hodges demonstrated the therapeutic effect of gonadal testosterone deprivation in the 1940s and therefore firmly established the concept that prostate cancer is a highly androgen-dependent disease. Since that time, hormonal therapy has undergone iterative advancement, from the types of gonadal testosterone deprivation to modalities that block the generation of adrenal and other extragonadal androgens, to those that directly bind and inhibit the androgen receptor (AR). The clinical states of prostate cancer are the product of a superimposition of these therapies with nonmetastatic advanced prostate cancer, as well as frankly metastatic disease. Today's standard of care for advanced prostate cancer includes gonadotropin-releasing hormone agonists (e.g., leuprolide), second-generation nonsteroidal AR antagonists (enzalutamide, apalutamide, and darolutamide) and the androgen biosynthesis inhibitor abiraterone. The purpose of this review is to provide an assessment of hormonal therapies for the various clinical states of prostate cancer. The advancement of today's standard of care will require an accounting of an individual's androgen physiology that also has recently recognized germline determinants of peripheral androgen metabolism, which include HSD3B1 inheritance.

Keywords: abiraterone; androgen deprivation therapy; androgens; enzalutamide; glucocorticoids; prostate cancer; steroids.

Graphical Abstract

Figure 1.

Pathways and enzymes to production of DHT. Steroid metabolism pathways and key enzymes for production of DHEA in the adrenal glands and conversion of DHEA to the potent androgen DHT in the prostate. Note that there are numerous isoforms of 17β-hydroxysteroid dehydrogenase; types 3 and 5 in particular are thought to be the important enzymes with reductive preference in prostate cancer (62).

Figure 2.

Adrenal-permissive HSD3B1(1245C) allele as a mechanism of treatment resistance. Prostate tumor growth is driven by activation of the AR by potent androgens. Castration cuts off the supply of gonadally produced androgens. Adrenally produced DHEA can be converted in prostate cells to potent androgens to restore AR activation and tumor growth. A key step in the conversion of DHEA is mediated by enzyme 3βHSD1, which depending on HSD3B1 genotype occurs in either a form that is readily ubiquitinated and degraded (adrenal-restrictive) or that is resistant to ubiquitination and degradation (adrenal-permissive) and therefore accumulates at higher levels in cells. With the adrenal-permissive form, DHEA is much more rapidly converted to downstream potent androgens leading to stronger AR activation and faster tumor growth. Created with Biorender.com.

Figure 3.

Alterations in glucocorticoid receptor pathway as a mechanism of enzalutamide resistance. Enzalutamide inhibits binding of androgens to the AR, suppressing transcription of AR-regulated genes and therefore suppressing prostate tumor growth (top). The GR regulates an overlapping but not identical set of genes as AR, therefore activating a subset of the AR-regulated genes. Increased GR expression, along with downregulation of enzyme 11β-hydroxysteroid dehydrogenase-2 that converts GR agonist cortisol to the inactive metabolite cortisone, can lead to increased transcription of this subset of AR-regulated genes and restoration of tumor growth (bottom). Created with Biorender.com.