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 non-metastatic 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), 2 nd-generation non-steroidal 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.

The tumor microenvironment and immune responses in prostate cancer patients

“…The androgen receptor is a crucial factor driving PCa progression, and anti-androgen therapies are a mainstay of treatment. Androgen deprivation therapies (ADT) reduce circulating testosterone by inhibiting gonadotrophin releasing homone, inhibiting the androgen receptor or androgen synthesis via inhibition of CYP17 (Desai et al 2021). The effect of both testosterone and androgen deprivation on the systemic and prostate immune responses is reviewed in (Ben-Batalla et al 2020;Gamat and McNeel 2017) -ADT induces alterations in circulating T cells, increasing naïve and Th1 cells with a concomitant reduction in CD4 + T regulatory cells (T regs ).…”

Dissecting the Hormonal Signaling Landscape in Castration-Resistant Prostate Cancer

“…Given the persisting role of the AR in the progression of PCa to the CRPC stage, inhibitors of the androgen pathways are commonly used for the treatment of CRPC patients [ 38 , 254 , 255 , 257 , 258 ]. Second-generation non-steroidal AR antagonists (enzalutamide, apalutamide, darolutamide) compete with androgens by binding to AR receptors and also inhibit AR translocation into the nucleus and its downstream binding to, and activation of, response elements in the promoter region of specific target genes.…”

“…Abufaraj and coworkers recently reported that, in patients with metastatic PCa, GnRH antagonists are associated with lower overall mortality rate (but without a significant difference in PSA progression) and cardiovascular events compared with GnRH agonists, while inducing higher injection site reactions [ 123 ]. Degarelix was shown to induce a more rapid decrease in testosterone levels and a better PSA control with respect to leuprolide in PCa patients [ 258 , 275 , 276 , 277 ]. Sugimura et al showed that switching from a GnRH agonist to an antagonist (degarelix) was associated with a delay in tumor progression in a case of CRPC [ 278 ]; moreover, a recent systematic meta-analysis has pointed out that treatment with degarelix after failure of a GnRH agonist is associated with decreased or stable PSA levels in patients progressing to the CRPC phase [ 279 ].…”

“…In accordance with these observations, ADT interventions, based on a gonadotropin-releasing hormone agonist, with or without an antiandrogen drug (AR antagonist or inhibitor of androgen synthesis), represent a mainstay treatment for PCa, even in the CRPC stage [ 255 , 257 , 258 ]. Recent clinical trials (PROSPER, SPARTAN, ARAMIS) reported a synergistic positive effect of AR antagonists (enzalutamide, apalutamide, darolutamide) and GnRH analog-based ADT on clinical outcomes (PSA levels and doubling time, median time to metastasis, PFS, OS, risk of death) in non-metastatic CRPC patients [ 262 , 293 , 294 , 295 , 296 ].…”

Fatty Acid Synthesis in Prostate Cancer: Vulnerability or Epiphenomenon?

“…Prostate adenocarcinoma is different from other cancer types because it is exquisitely dependent on signaling through the androgen receptor (AR). Androgen deprivation therapy (ADT) is arguably the most effective systemic therapy targeting one pathway for any cancer type with a response rate of about 90% when synthesis of androgens is blocked from both the testes and adrenal glands (13,14). When prostate cancer recurs after ADT (i.e.…”