Prostate Cancer Hormonal therapy Comprehensive Review Article Part 6

Prostate Cancer Hormonal therapy Comprehensive Review Article Part 6 Prof. Dr. Semir. A. Salim. Al Samarrai Hormonal therapy: Different types of hormonal therapy The hormonal therapy is the fourth modality of PCA treatment, there are different types of hormonal therapy. Androgen deprivation can be achieved by suppressing the secretion of testicular androgens in different ways. This can be combined with inhibiting the action of circulating androgens at the level of their receptor which has been known as complete (or maximal or total) androgen blockade (CAB) using the old-fashioned antiandrogens [1]. Testosterone-lowering therapy (castration): Castration level The testosterone-lowering therapy (castration) aims to decrease the testosterone level to castration level, which means the castration level of testosterone is < 50 ng/dL (1.7 nmol/L), which was defined more than 40 years ago when testosterone testing was less sensitive. Current methods have shown that the mean value after surgical castration is 15 ng/dL [2]. Therefore, a more appropriate level should be defined as < 20 ng/dL (1 nmol/L). Bilateral orchiectomy The castration modality with Bilateral orchiectomy or subcapsular pulpectomy is still considered the primary treatment modality for ADT. It is a simple, cheap and virtually complication-free surgical procedure. It is easily performed under local anaesthesia, and it is the quickest way to achieve a castration level which is usually reached within less than twelve hours. It is irreversible and therefore does not allow for intermittent treatment [3]. Oestrogens One of the hormonal therapy modality is the treatment with oestrogens results in testosterone suppression and is not associated with bone loss [4]. Early studies tested oral diethylstilboestrol (DES) at several doses. Due to severe side effects, especially thromboembolic complications, even at lower doses these drugs are not considered as standard first-line treatment [5–7]. Luteinising-hormone-releasing hormone agonists Long-acting LHRH agonists are currently the main forms of ADT. These synthetic analogues of LHRH are delivered as depot injections on a 1-, 2-, 3-, 6-monthly, or yearly, basis. The first injection induces a transient rise in luteinising hormone (LH) and follicle-stimulating hormone (FSH) leading to the ‘testosterone surge’ or ‘flare-up’ phenomenon which starts two to three days after administration and lasts for about one week. This may lead to detrimental clinical effects (the clinical flare) such as increased bone pain, acute bladder outlet obstruction, obstructive renal failure, spinal cord compression, and cardiovascular death due to hypercoagulation status [8]. Luteinising-hormone-releasing hormone antagonists Luteinising-hormone-releasing hormone antagonists immediately bind to LHRH receptors, leading to a rapid decrease in LH, FSH and testosterone levels without any flare. The practical shortcoming of these compounds is the lack of a long-acting depot formulation with, so far, only monthly formulations being available. Degarelix is a LHRH antagonist. The standard dosage is 240 mg in the first month followed by monthly injections of 80 mg. Most patients achieve a castrate level at day three [9]. Relugolix is an oral gonadotropin-releasing hormone antagonist. It was compared to the LHRH agonist leuprolid in a randomised phase III trial [10]. The primary endpoint was sustained testosterone suppression to castrate levels through 48 weeks. There was a significant difference of 7.9 percentage points (95% CI: 4.1–11.8) showing non-inferiority and superiority of relugolix. The incidence of major adverse cardiovascular events was significantly lower with relugolix (prespecified safety analysis). Relugolix has been approved by the FDA [11]. The anti-androgens The anti-androgens are oral compounds and classified according to their chemical structure as: • steroidal, e.g., cyproterone acetate (CPA), megestrol acetate and medroxyprogesterone acetate; • non-steroidal or pure, e.g., nilutamide, flutamide and bicalutamide. Both classes compete with androgens at the receptor level. This leads to an unchanged or slightly elevated testosterone level. Conversely, steroidal anti-androgens have progestational properties leading to central inhibition by crossing the blood-brain barrier. The steroidal anti-androgens These compounds are synthetic derivatives of hydroxyprogesterone. Their main pharmacological side effects are secondary to castration (gynaecomastia is quite rare) whilst the non-pharmacological side effects are cardiovascular toxicity (4–40% for CPA) and hepatotoxicity. Non-steroidal anti-androgens Non-steroidal anti-androgen monotherapy with e.g., nilutamide, flutamide or bicalutamide does not suppress testosterone secretion and it is claimed that libido, overall physical performance and bone mineral density (BMD) are frequently preserved [12]. Non-androgen-related pharmacological side effects differ between agents. Bicalutamide shows a more favourable safety and tolerability profile than flutamide and nilutamide [800]. The dosage licensed for use in CAB is 50 mg/day, and 150 mg for monotherapy. The androgen pharmacological side effects are mainly gynaecomastia (70%) and breast pain (68%). However, non-steroidal anti-androgen monotherapy offers clear bone protection compared with LHRH analogues and probably LHRH antagonists [12,13]. All three agents share the potential for liver toxicity (occasionally fatal), requiring regular monitoring of patients’ liver enzymes. New androgen pathway targeting agents (ARTA) Once on ADT the development of castration-resistance (CRPC) is only a matter of time. It is considered to be mediated through two main overlapping mechanisms: androgen-receptor (AR)-independent and AR-dependent mechanisms. In CRPC, the intracellular androgen level is increased compared to androgen sensitive cells and an over-expression of the AR has been observed, suggesting an adaptive mechanism [14]. This has led to the development of several new compounds targeting the androgen axis. In mCRPC, AAP and enzalutamide have been approved. In addition to ADT (sustained castration), AAP, apalutamide and enzalutamide have been approved for the treatment of metastatic hormone sensitive Pca (mHSPC) by the FDA and the EMA. For the updated approval status see EMA and FDA websites [15–19]. Finally, apalutamide, darolutamide and enzalutamide have been approved for non-metastatic CRPC (nmCRPC) at high risk of further metastases [20–24]. Abiraterone acetate Abiraterone acetate is a CYP17 inhibitor (a combination of 17α-hydrolase and 17,20-lyase inhibition). By blocking CYP17, abiraterone acetate significantly decreases the intracellular testosterone level by suppressing its synthesis at the adrenal level and inside the cancer cells (intracrine mechanism). This compound must be used together with prednisone/prednisolone to prevent drug-induced hyperaldosteronism [15,18]. Apalutamide, darolutamide, enzalutamide (alphabetical order) These agents are novel non-steroidal anti-androgens with a higher affinity for the AR receptor than bicalutamide. While previous non-steroidal anti-androgens still allow transfer of ARs to the nucleus and