Androgen deprivation therapy for the treatment of prostate cancer: a focus on pharmacokinetics

Abstract

Medical therapy has undergone many changes as our understanding of prostate cancer cell biology has improved. Androgen deprivation therapy (ADT) remains the mainstay of therapy for metastatic disease. Metastatic castrate-resistant prostate cancer (CRPC) is an important concern since we are unable to stop progression with currently available agents. Areas covered: Pharmacologic ADT is the most commonly used treatment for metastatic prostate cancer. Multiple agents are available for both first-line and second-line use: antiandrogens, estrogens, luteinizing hormone-releasing hormone agonists/antagonists, and CYP17 inhibitors. With adoption of these drugs, it is important to consider their pharmacokinetic and pharmacodynamic properties. Many undergo metabolism through cytochrome P450. Levels may be altered with co-administration of drugs acting as enzyme inhibitors or inducers. Understanding mechanism of action, metabolism, and excretion of these drugs allows clinicians to provide the best therapeutic care while minimizing adverse events. Expert opinion: Many men with metastatic prostate cancer will progress to castration resistance. An understanding of resistance mechanisms at the cellular level has revealed new drug targets with hopes of halting or reversing progression of metastatic disease. Second-line agents, traditionally reserved for CRPC, are being studied in metastatic castrate-sensitive prostate cancer, and may offer practice-changing evidence supporting their use.

Characterization of iPS87, a prostate cancer stem cell-like cell line

“…Since patients' prostate cancer cells are thought to overexpress the AR, one basic treatment for recurrent systemic disease, is breaking the Androgen-AR pathway. Clinically, the pathway is broken by suppressing the availability of testosterone via the use of Luteinizing Hormone-Releasing Hormone (LHRH) agonists [35,36]. This method inhibits Luteinizing Hormone (LH) release from the anterior pituitary, and results in the inability of Leydig cells to produce testosterone [37].…”

“…This method inhibits Luteinizing Hormone (LH) release from the anterior pituitary, and results in the inability of Leydig cells to produce testosterone [37]. Effective suppression of recurrent prostate cancer cell proliferation by interrupting this pathway has necessitated the synthesis of multiple, specific and effective drugs with anti-hormone and/or anti-AR activity including estrogens, LHRH agonists, and more [36]. ADT has been successful, in that the treatments showed destruction via apoptosis or cell cycle death of prostate cancer cells [37].…”

Cancer Treatment–Induced Bone Loss in Women With Breast Cancer and Men With Prostate Cancer

“…In pre- and perimenopausal women, estrogen production may be manipulated by use of gonadotropin-releasing hormone (GnRH) agonists or by surgical removal of ovaries. GnRH agonists are given as intramuscular or subcutaneous injections and lead to regulation of gonadotropin receptors at the level of the anterior pituitary, reducing estrogen and testosterone production [ 13 ]. Thus, this is an important mechanism in hormone-sensitive breast tumors (those expressing estrogen/progesterone receptors, ER/PR+) in premenopausal BCa, in which ~60% of cases of BCa are hormone receptor positive, which is less than the ~80% of cases BCa in postmenopausal women [ 14 ].…”

Role of the androgen signaling axis in genitourinary malignancies

“…However, nearly all of these men progress to the hormone-refractory state of castrate-resistant prostate cancer (CRPC), which inevitably results in death. The initial treatment response to ADT is limited, as tumor cells evolve complicated mechanisms to reactivate the AR signaling axis, including AR amplification, gene mutations, splice- variant pathways, and aberrant co-regulator activities (9,10). A thorough understanding of the androgen signaling axis led to the development of second-line hormonal therapies that exploit this continued influence of androgen, even in the castrate-state (7).…”