Introduction

Prostate cancer (PCa) is the most prevalent cancer in men; median survival of patients with newly diagnosed metastases is 4 years (EAU Guidelines 2017; James et al. 2015).

In the 1940s, Huggins and Hodges showed the responsiveness of prostate cancer to androgen deprivation therapy (ADT); since this time, androgen-suppressing strategies are the basis of any management of advanced and metastatic prostate cancer (Huggins and Hodges 1972; EAU Guidelines 2017).

Testosterone suppression can be achieved by orchidectomy, estrogens, luteinizing hormone-releasing hormone (LHRH) agonists, and gonadotropin-releasing hormone (GNRH) antagonists. Anti-androgens inhibit the action of circulating androgens at the level of their receptor. The normal testosterone concentration in man is age-dependent and is subject to daily fluctuations, with medical or surgical castration serum testosterone levels fall to <50 ng/dL (<1.73 nmol/l).

ADT is increasingly used in earlier disease stages. Multiple phase III randomized trials demonstrated a significant survival benefit for men with locally advanced or high-risk localized prostate cancer when treated with a combination of Radiotherapy (RT) with ADT compared to RT alone (Bolla et al. 2010; Pilepich et al. 2005).

For men treated for advanced prostate cancer, initial response to androgen withdrawal is high; however, this response is only temporary and almost all patients will develop a castrate resistant disease.

Prognostic factors for survival include parameters like number and location of bone metastases, presence of visceral metastases, Gleason score, performance status, and serum parameters like initial PSA, alkaline phosphates, and hemoglobin as well as PSA-response after ADT (Glass et al. 2003; Gravis et al. 2015).

For men with metastatic hormone naive prostate cancer, combined treatment with a combination of chemotherapy with docetaxel and ADT has demonstrated a significant survival benefit, and this combination is now considered standard of care (Sweeney et al. 2015; EAU Guidelines 2017; NCCN Guideline 2017).

For men with castrate-resistant prostate cancer (CRPC), new treatment options with overall survival benefit are available including Abiraterone and Enzalutamide, nonhormonal therapies like chemotherapy with docetaxel and Cabazitaxel, Vaccine, and Radium-223. According to the recent guidelines, androgen deprivation therapy should be continued; this recommendation applies to metastatic CRPC and nonmetastatic CRPC (Merseburger et al. 2015).

Androgen Deprivation Treatment (ADT)

The current treatment for localized, early stage prostate cancer involves either surgery, radiation, active surveillance, or watchful waiting, while the standard treatment for patients with hormone-sensitive metastatic disease is either medical castration with a luteinizing hormone-releasing hormone (LHRH) agonists, gonadotropin-releasing hormone (GNRH) antagonists, or surgical castration by orchiectomy, either alone or in combination with an anti-androgen.

In 1941, Huggins et al. demonstrated the favorable impact of androgen deprivation therapy (ADT) on metastatic prostate cancer (mPCa) (Huggins and Hodges 1972). However, hormone ablation represents a palliative treatment for advanced prostate cancer.

Mechanism of Hormonal Treatment

Growth of prostate cells is androgen-dependent. Testosterone, dehydroepiandrosterone, and androstenedione provide their growth-promoting influence on the prostate cell via the androgen receptor. Ninety percent of androgens are produced in the Leydig cells of the testes, 10% are additionally released by the adrenal cortex (Harris et al. 2009; Chang et al. 2014).

Androgen synthesis is regulated through hypothalamic and pituitary influence. Luteinizing releasing hormone (LHRH) is formed in the hypothalamus and causes the formation and release of the gonadotropins LH (luteinizing hormone) and FSH (follicular-stimulating hormone) from the pituitary anterior lobe. LH stimulates the Leydig intermediate cells to grow and produce androgens. FSH promotes spermiogenesis in man and increases formation of testosterone in the Sertoli cells (Luu-The et al. 2008).

All these mechanisms result in an androgenic release, which in turn controls the hypothalamus-pituitary axis through feedback mechanisms.

Only approximately 10% of the circulating testosterone is unbound (FT), the majority of released testosterone is bound to SHBG (sex hormone binding globulin) or albumin.

In the prostate, testosterone is converted into dihydrotestosterone, which has a significantly higher affinity for the intracellular androgen receptor than testosterone (Chang et al. 2014).

Testosterone-Lowering Therapy (Castration)

Bilateral Orchiectomy

Surgical castration is a primary treatment modality for ADT. It leads to a rapid decline in testosterone levels <50 ng/dL (1.7 nmol/L).

Current analytical methods have shown that the mean testosterone levels after surgical castration is 15 ng/dL (Oefelein et al. 2000). Therefore, a lower level of testosterone <20 ng/dL as definition for castrate level may be more appropriate than the historical <50 ng/dL (1.7 mmol/L).

Bilateral orchiectomy can be performed under local anesthesia (Desmond et al. 1988) and results in castrate levels of testosterone within 12 h; however studies have demonstrated that it leads to more psychological stress compared to medical castration (Nicholson 1986). The majority of patients with advanced or metastatic prostate cancer shows a drug-induced hormonal ablation.

Medical Androgen Depletion

Medical androgen depletion can be achieved by inhibiting testosterone production or by blocking the androgen receptors while maintaining testosterone production. The inhibition of androgen production is achieved by the use of LHRH agonists, LHRH antagonists, and estrogens.

Luteinizing-Hormone-Releasing Hormone (LHRH) Agonists

The luteinizing-releasing hormone (LHRH) is a synthetic decapeptide, which was discovered in 1971. It is secreted in a pulsatile manner by the hypothalamus and has a half-life of 2–5 min (Seidenfeld et al. 2000).

LHRH analogues bind to the LHRH receptor with high affinity resulting in increased secretion of FSH and LH and increased testosterone production.

The constant receptor stimulation results in a down-regulation of the pituitary receptor with a paradoxical and sustained drop in gonadotropin secretion. This downregulation occurs after 7–10 days. While this phase is reversible, it can be maintained when GnRH agonists treatment is continued (Seidenfeld et al. 2000).

Since 1980, LHRH analogues have been used for clinical purposes. Synthetic long-acting LHRH agonists are the most commonly used forms of ADT.

These analogues of LHRH were initially administered by daily subcutaneous injections or nasal inhalations. Today long-acting depot formulations with 1-, 2-, 3-, 6-monthly or yearly basis are used and have significantly improved the compliance of treatment.

The different products have practical differences that need to be considered in daily practice, including optimal storage temperature, whether a drug is ready for immediate use or requires reconstitution, and whether a drug is given by subcutaneous or intramuscular injection (EAU Guidelines 2017).

It is important to carefully follow the directions for using a particular drug to avoid any misuse.

No direct comparison exists between the different agonists; however, they are considered equally effective and sufficient testosterone suppression is usually obtained after 2–4 weeks (Klotz et al. 2008).

The “flare-up” at the beginning of the treatment with increased testosterone production may lead to a clinical “flare phenomenon” in advanced disease which may include increased bone pain, acute bladder outlet obstruction, obstructive renal failure, spinal cord compression, and fatal cardiovascular events due to hypercoagulation status and delays the therapeutic benefit. Patients at risk are patients with high-volume, symptomatic bony disease, which account for 4–10% of metastatic patients. To prevent “flare-up,” anti-androgens should be started one week before administration of the LHRH analogue and should be continued for a 2-week period (EAU guideline 2017).

Gonadotropin-Releasing Hormone (GnRH) Antagonists

These receptor blockers antagonize the gonadotropin-releasing hormone receptor (GnRHR) in the pituitary and thus the action of GnRH. GnRH antagonists compete with natural GnRH for binding to GnRH receptors; thus decreasing or blocking GnRH action leading to a rapid decrease in LH, FSH, and testosterone levels.

Unlike the LHRH agonists, which cause an initial stimulation of the hypothalamic-pituitary-gonadal axis, leading to a surge in testosterone levels, GnRH antagonists have an immediate onset of action, rapidly reducing sex hormone levels without an initial surge (Van Poppel and Nilsson 2008; EAU Guidelines 2017).

Currently approved GnRH antagonists include the following four drugs:

Degarelix, Abarelix, Cetrorelix, and Ganirelix; these are administered either by intramuscular injection or by subcutaneous injection. Elagolix, a non-peptide, orally-active GnRH antagonist which is still in development, is administered orally.

The practical shortcoming of these compounds is the lack of a long-acting depot formulation with only monthly formulations being available.

Degarelix, which is the most commonly used component, is an LHRH antagonist with a monthly subcutaneous formulation. 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 3 (Crawford et al. 2011). Data suggest a lower cardiotoxicity compared to orchiectomy or LHRH analoga (Albertsen et al. 2014).

Estrogens

Estrogens were the first substances used as an alternative to orchiectomy for the hormonal treatment of metastatic prostate cancer.

They resulted in a drop of LH serum level and consequently of testosterone level within several weeks. However, increased cardiovascular complications, which were dose-dependent, were observed in the therapy with estrogens. Due to the cardiotoxicity, estrogens are not considered as standard treatment (EAU Guidelines 2017).

Antiandrogens

These compounds are classified according to their chemical structure as.

Steroidal antiandrogens, e.g., cyproterone acetate (CPA), megestrol acetate, and medroxyprogesterone acetate and nonsteroidal, e.g., bicalutamide, flutamide, and nilutamide, which lead to an unchanged or slightly elevated testosterone level. Younger patients may benefit from such treatment, as side effects like libido and erectile dysfunction are less often observed. Side effects of the nonsteroidal antiandrogens include gynecomastia and mastodynia; liver function disorders may also occur with potential severe liver toxicity (EAU Guidelines 2017).

Steroidal Antiandrogens

Steroidal antiandrogens influence LH release due to the additional progesterone-like effect, thus inhibiting testosterone production. Both compounds compete with endogenous androgens for binding on the androgen receptor (Cornford et al. 2017).

Cyproterone Acetate

Cyproterone acetate is an antiandrogen and progestogen; it is available orally and i.m. with a half-life of 40 h. It was first marketed in 1973 and was the first antiandrogen to be introduced for medical use. The drug is available widely throughout the world, but is not approved for use in the United States (Index Nominum 2000).

It blocks the effect of testosterone as well as testosterone production. Side effects include gynecomastia and feminization in general, sexual dysfunction, mental symptoms like depression, fatigue, liver toxicity, and adrenal insufficiency.

Nonsteroidal Antiandrogens

Nonsteroidal antiandrogens do not suppress testosterone secretion, and this may preserve libido, overall physical performance, and bone mineral density (Smith et al. 2004).

Bicalutamide

Bicalutamide is the most widely used antiandrogen in the treatment of prostate cancer. It is well-absorbed, the half-life is 6 days. It is approved at a dosage of 50 mg/day as combination therapy with a LHRH analogue or orchiectomy and as monotherapy at a dosage of 150 mg/day for the treatment of stage C or D1 locally advanced prostate cancer. Bicalutamide is not indicated for the treatment of localized prostate cancer due to negative findings in the Early Prostate Cancer (EPC) trial (Wellington and Keam 2006; Wirth et al. 2004).

Common side effects include breast enlargement, breast tenderness, hot flashes, and constipation as well as feminization and changes in mood and liver as well as lung toxicity; monitoring of liver enzymes is recommended during treatment (Schellhammer and Davis 2004).

Flutamide

Flutamide is a synthetic, nonsteroidal antiandrogen (NSAA), which has been largely replaced by newer NSAAs, namely, bicalutamide due to better safety, tolerability, and pharmacokinetic profiles. Flutamide has been studied as monotherapy. Flutamide is a pro-drug, and the half-life of the active metabolite is 5–6 h, leading to a three times daily use. The recommended daily dosage is 750 mg. The non-androgen pharmacological side-effect of flutamide is diarrhea and hepatotoxicity; it does not appear to have a risk of cardiovascular side effects (Goldspiel and Kohler 1990).

Extragonadal ablation of androgen synthesis from precursors through inhibition of cytochrome P450 17α-hydroxy/17,20-lyase (CYP17) enzymes like Abiraterone have already been approved for men with mCRPC. Newer CYP17 inhibitors like orteronel and galeterone continue to be developed which are either more selective or have concomitant inhibitory actions on AR signaling (Cornford et al. 2017).

Abiraterone Acetate

Abiraterone acetate (AA) is a CYP17 inhibitor (a combination of 17 hydrolase and 17–20 lyase inhibition). By blocking CYP17, AA 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 (2 × 5 mg) to prevent drug-induced hyperaldosteronism.

Based on the results of the COU-AA-301 trial, the FDA approved the use of Abiraterone for the treatment of mCRPC in the post-chemotherapy setting in April 2011 (De Bono et al. 2011). The COU-AA 301 trial observed an overall survival (OS) benefit, increase in time to prostate-specific antigen (PSA) progression and progression-free survival (PFS) (median OS, 15.8 versus 11.2 months; median time to PSA progression, 8.5 versus 6.6 months; median radiologic PFS, 5.6 versus 3.6 months). Later studies have demonstrated its efficacy in chemotherapy-naïve patients with mCRPC. In a phase III randomized trial with a median follow up of more than 4 years, treatment with AA prolonged OS compared with prednisone alone (34.7 versus 30.3 months; hazard ratio (HR), 0.81), suggesting its favorable efficacy and safety profile in CRPCa chemotherapy-naive patients as well (Ryan et al. 2015).

Orteronel

Orteronel (TAK-700) is an oral, nonsteroidal CYP17A1 inhibitor. It completed two phase III clinical trials for metastatic, hormone-refractory prostate cancer but failed to extend overall survival rates, and development was voluntarily terminated as a result (Alex et al. 2016).

However, when men were stratified by regions, a significant improvement in OS was seen in men in the non-Europe/North American regions (15.3 versus 10.1 months, p = 0.019), despite having similar baseline clinical and disease characteristics. This discrepancy in OS by region may have been related to the decreased exposure to post-trial treatment with AA and enzalutamide, as these agents were available earlier in North American and European regions (Alex et al. 2016; Poorthuis et al. 2017).

Galeterone

Galeterone is a CYP17 inhibitor with multiple mechanisms of action, including CYP17 inhibition, AR antagonism, and decrease in intratumoral AR levels. Preclinical results indicate that treatment with Galeterone caused marked downregulation of AR protein expression, in contrast to treatments with bicalutamide or androgen deprivation therapy (ADT), which may induce upregulation of AR protein expression. It also caused a significant reduction in tumor growth compared with AA (Alex et al. 2016; Poorthuis et al. 2017).

Ketoconazole

Ketoconazole is a synthetic imidazole antifungal drug used primarily to treat fungal infections.

Ketoconazole inhibits the activity of several enzymes necessary for the conversion of cholesterol to steroid hormones through inhibition of 17α-hydroxylase and 17,20-lyase. Based on these antiandrogen and antiglucocorticoid effects, ketoconazole has been used with some success as a second-line treatment for certain forms of advanced prostate cancer (Zelefsky et al. 2008). Ketoconazole is an androgen receptor antagonist, competing with androgens such as testosterone and dihydrotestosterone (DHT) for binding to the androgen receptor.

However, in the treatment of prostate cancer, concomitant glucocorticoid administration is needed to prevent adrenal insufficiency (Mahler et al. 1993).

In 2013, the European Medicines Agency’s Committee on Medicinal Products for Human Use (CHMP) recommended not to use oral ketoconazole for systemic use in humans throughout the European Union, after concluding that the risk of serious liver injury from systemic ketoconazole outweighs its benefits.

The recent NCCN guideline still recommends its use as an option for men with metastatic CRPCA (NCCN guideline 2017).

Enzalutamide

Enzalutamide is a synthetic nonsteroidal antiandrogen with a half-life of 8–9 days and a higher affinity than bicalutamide for the AR receptor. In 2012, the FDA approved enzalutamide for the treatment of castration-resistant prostate cancer based on the results of the AFFIRM trial (Scher et al. 2012). Enzalutamide induces enzyme activity of CYP3A4, CYP2C9, and CYP2C19.

Side effects of enzalutamide include gynecomastia, breast pain, fatigue, diarrhea, hot flashes, headache, sexual dysfunction, and seizures. Other side effects include neutropenia, anxiety, cognitive disorder, memory impairment, hypertension, dry skin, and pruritus (Tombal et al. 2015).

Apalutamid

Apalutamide (ARN-509, JNJ-56021927) is a nonsteroidal antiandrogen and selective competitive antagonist of the androgen receptor. It has a 5- to ten-fold greater affinity for the AR compared to bicalutamide. Apalutamide is currently tested in phase III clinical trials in men with castration-resistant prostate cancer. Based on the positive findings in the PHASE III Trial SPARTAN in men with M0 CRPCA, this drug is approved for treatment in men with short PSA-doubing time and no evidence for metastatic disease (N Engl J Med. 2018 Apr 12;378(15):1408-1418).

Apalutamide may also be effective in a subset of prostate cancer patients with acquired resistance to abiraterone acetate. Apalutamide shows potent induction potential of CYP3A4 similarly to enzalutamide (Fizazi et al. 2015).

Complete Androgen Blockade (CAB)

The CAB (also known as Maximum Androgen Blockade (MAB)) includes the additional administration of an antiandrogens for hormonal ablation followed by orchiectomy or administration of an LH-RH analogue. A clinical benefit in the primary therapy of metastatic hormonal prostate carcinoma has been studied in numerous studies.

Antiandrogens produce an inhibition of ligand binding of the androgen receptor and an inhibition of androgen-independent activation of the receptor. Over the last 25 years, more than 30 clinical trials of CAB versus monotherapy have been published.

The largest randomized controlled trial in 1286 M1b patients found no difference between surgical castration with or without flutamide (Eisenberger et al. 1998).

The Prostate Cancer Trialists’ Collaboration Group meta-analysis on the MAB demonstrated a nonsignificant 2% benefit in 5-year survival in patients with a maximum androgen blockade (Schmitt et al. 2000). While the subgroup analysis of MAB with nilutamide or flutamide resulted in a significant 5-year survival benefit in favor of the complete blockade of 3%; this advantage in a small subset of patients must be balanced against the increased side effects associated with long-term use of NSAAs.

Intermittent Androgen Deprivation Therapy (IAD)

The intermittent androgen blockade includes an induction phase with ADT over a period of 6–9 months. If a response to therapy is seen, treatment is stopped to allow testicular function to recover.

This may result in a potential decrease in specific side effects like, e.g., hot flushes and an improvement in erectile function, bone health, and quality of life.

When tumor progression is observed under normalized testosterone values, a new treatment with ADT is started. Multiple reviews (Niraula et al. 2013; Sciarra and Salciccia 2014; Botrel et al. 2014) and a meta-analysis (Brungs et al. 2014) analyzed the clinical efficacy of IAD.

So far, the SWOG 9346 (Hussain et al. 2013) is the largest trial conducted in M1b patients. Out of 3040 selected patients in the SWOG 9346 trial, 1535 were randomized based on the inclusion criteria set. This non-inferiority trial led to inconclusive results, the pre-specified non-inferiority limit was not achieved, and the results did not show a significant inferiority for any treatment arm. However, inferior survival with IAD cannot be completely ruled out based on this study.

Other trials did not show any survival difference. These reviews and the meta-analysis concluded that there was no difference in OS or CSS between IAD and continuous androgen deprivation but a trend favoring IAD in terms of QoL, especially regarding treatment-related side effects (Verhagen et al. Verhagen et al. 2014).

According to the EAU, guidelines following recommendations can be made: The induction cycle should be 6–9 months; ADT should be stopped only if patients is well-informed and compliant, and no clinical progression and clear PSA response is seen, empirically defined as a PSA < 4 ng/mL in metastatic disease. Treatment with ADT is restarted when the patient progresses clinically or has a PSA rising above a predetermined threshold (Sciarra and Salciccia 2014).

Side Effects of Androgen Deprivation

By lowering testosterone serum level to the level of the castration, specific side effects like physical weakness, fatigue, hot flashes, loss of libido, erectile dysfunction, gynecomastia, mood swings, anemia, and osteoporosis may occur.

A systematic review of side-effects of long-term ADT has recently been published by Ahmadi and Daneshmand (2013).

Hot flushes are one of the most common side-effect of ADT and will significantly influence QoL. Other systemic side-effects of androgen-deprivation therapy include nonmetastatic bone fractures with an increased risk of up to 45% with long-term ADT (Smith et al. 2006).

An evaluation of Bone Mineral Density (BMD) should be performed in patients at risk by dual emission X-ray absorptiometry (DEXA) scan before initiating long-term ADT. An initial low BMD indicates a high risk of subsequent nonmetastatic fracture. For evaluating individual risk, WHO FRAX tool (http://www.shef.ac.uk/FRAX) should be used (EAU Guidelines 2017).

Metabolic effects include lipid alterations as well as also decreased insulin sensitivity and increases fasting plasma insulin levels and increased risk for the metabolic syndrome (Saylor and Smith 2009; Grundy et al. 2005).

Metabolic syndrome is an association of cardiovascular disease risk factors. The definition requires at least three of the following criteria like waist circumference >102 cm; serum triglyceride >1.7 mmol/L; blood pressure >130/80 mmHg or use of medication for hypertension; High-density lipoprotein (HDL) cholesterol <1 mmol/L; glycemia >5.6 mmol/L or the use of medication for hyperglycemia.

The published data regarding cardiovascular morbidity are inconclusive.

ADT is associated with an increased risk of diabetes mellitus, cardiovascular disease, and myocardial infarction (Keating et al. 2010). However, the RTOG 92-02 trial demonstrated no increase in cardiovascular mortality in men with locally advanced prostate cancer with longer duration of adjuvant LHRH therapy (Efstathiou et al. 2008).

It has been suggested that LHRH antagonists might be associated with less cardiovascular morbidity compared to agonists (Albertsen et al. 2014).

However, to reduce the cardiovascular risk, patients should be encouraged to adopt lifestyle changes with increased physical activity, cessation of smoking, decreased alcohol consumption, and normalization of BMI (EAU Guidelines 2017).

Primary ADT for Nonmetastatic Prostate Cancer

Treatment with curative intent includes surgery and radiation therapy as well as delayed treatment with active surveillance.

If a patient decides against a therapy with curative intent, he should be informed about the concept of watchful waiting with symptom-dependent palliative intervention and an immediate ADT. Patients should understand that both options are palliative and that the immediate ADT is associated with adverse effects (EAU Guidleine 2017).

Immediate ADT is associated with improved progression-free survival but the effect on overall survival for men with nonmetastatic prostate cancer is unclear (Studer et al. 2006).

Neoadjuvant ADT of Localized Prostate Cancer Prior to Surgical Therapy

The goal of neoadjuvant as well as adjuvant therapy is to improve long-term survival for patients with high-risk disease. Neoadjuvant therapy may also provide a down-staging of locally advanced prostate cancer and improve surgical resection.

To assess the effect of neoadjuvant combination, ADT administered for 3 months before radical prostatectomy; Labrie et al. performed a prospective trial using leuprolide and flutamide for 3 months prior to RP compared to RP alone (Labrie et al. 1997).

The study showed that neoadjuvant combination ADT decreased positive surgical margins from 33.8% to 7.8% and resulted in down-staging in 54% in the neoadjuvant arm. In addition, pCRs were found in six RP specimens (6.7%). The authors concluded that the influence of neoadjuvant combination therapy on the stage of the disease suggests a major improvement in the morbidity and mortality from prostate cancer and that longer duration of neoadjuvant ADT could potentially increase the degree of benefit (Labrie et al. 1997).

A systematic review and meta-analysis of randomized trials of neo-adjuvant hormone therapy (NHT) in localized and locally advanced prostate cancer showed that neoadjuvant therapy had a beneficial and statistically significant impact in lowering the pathologic T stage, increasing the organ-confined rate, lowering the positive surgical margin rate, and decreasing the number of pathologic N1 cases (Shelley et al. 2009).

The effect on positive surgical margins and organ-confined rates was significantly better with 8 months of neoadjuvant treatment as compared to only 3 months of treatment.

However, NHT prior to prostatectomy did not improve overall or disease-free survival. The beneficial effects on pathologic outcomes did not translate to improved DFS or OS. The DFS at 5 years, defined either as biochemical or clinical progression, remained unchanged between the treatment and control groups. The authors concluded that NHT is associated with significant clinical benefit when given with radiotherapy and improves pathological outcome prior to prostatectomy but is of minimal value prior to radical prostatectomy. The decision to use hormone therapy should be discussed between the patient, the clinician, and policy maker based on the benefits, toxicity, and cost.

Based on these findings, the recent guidelines do not recommend the use of neoadjuavant ADT before surgery. Approval of neoadjuvant therapy prior to RP in patients with high-risk prostate cancer will depend on positive results from well-designed phase III trials (McKay et al. 2013).

Adjuvant Androgen Ablation in Men with Localized Prostate Carcinoma After Surgical Therapy

Whether adjuvant treatment options improve overall survival for men treated with radical prostatectomy has been studied in various prospective randomized trials. One of the largest prospective studies was the Early Prostate Cancer (EPC) study, which examined the effect of adjuvant administration of bicalutamide (150 mg per day) versus standard care in different patient groups (Wirth et al. 2004).

For locally advanced tumors, after an average follow-up period of 7.4 years, an advantage could be shown in the clinical progression-free survival; no significant difference was found in overall survival.

A similar result was demonstrated by the trial with the antiandrogen flutamide in the dosage 3 × 250 mg; even after a median follow-up of 6.1 years, no difference in overall survival was seen; however, an improved progression-free survival was found.

The prospective randomized study by Messing et al. investigated the effect of immediate adjuvant hormonal therapy versus a delayed hormonal therapy at the time of clinical progression in patients with lymph node metastases who had received a radical prostatectomy with lymphadenectomy (Messing et al. 2006).

This study demonstrated a clear survival benefit for patients with lymph node metastases for immediate adjuvant hormone therapy.

However, this study was criticized for several reasons; on the one hand, the number of patients being 98 was low and patients included in this trial had high-volume N+ disease and adverse tumor parameters, and, on the other hand, patients in the control arm did not receive hormone therapy at the time of PSA progression but only at clinical progression.

According to the recent guidelines, should the possible benefits be judged against the potential side effects of long-term HT. Delaying the initiation of HT until PSA progression is an acceptable option in selected cases with <2 microscopically involved lymph nodes in an extended nodal dissection EAU Guidelines (2017).

Neoadjuvant/Adjuvant ADT for Localized and Locally Advanced Prostate Cancer in Men Treated with Radiation Therapy

Whether neoadjuvant and/or adjuvant ADT improves the results of radiation therapy in prostate cancer has also been investigated in numerous prospective randomized studies. These trials included high-risk PCa patients, mostly locally advanced prostate cancer (T3-T4 N0-X), as well as high-risk localized, T1-2, N0-X prostate cancer. The most powerful conclusion from these studies comes from the EORTC 22863 trial, which is the basis for the combination of RT and ADT in patients with locally advanced PCa as standard of care (Bolla et al. 2009).

For men with medium- or high-risk prostate cancer, these trial have demonstrated a clear survival advantage for additional ADT.

The current guidelines therefore recommend neoadjuvant and adjuvant hormonal therapy before and after radiotherapy in patients with localized prostate carcinoma and high risk according to the D’Amico classification as well as in patients with locally limited prostate carcinoma and intermediate risk (Hernandez et al. 2007).

However, the optimal duration of adjuvant hormone therapy after radiotherapy has not yet been conclusively clarified.

The data of Bolla et al. show that adjuvant therapy for 3 years significantly improves survival, but there are open questions about the hormone withdrawal with regard to the type of hormone therapy (LHRH-agonists alone versus maximum androgen blockade or testosterone receptor blockade alone or GNRH-antagonists).

According to the recent guidelines, ADT is started either at the onset of RT (for adjuvant ADT) or 2 or 3 months before (for neoadjuvant) long-term ADT, ranging from 2 to 3 years, is recommended for locally advanced disease rather than short term (6-months) (Bolla et al. 2009; Denham et al. 2011).

If a long-term ADT is necessary in patients with intermediate- or high-risk localized PCa is unclear. The use of short-term ADT for 4 months before and during radiotherapy was associated with significantly decreased disease-specific mortality and increased overall survival (RTOG 94-08). According to post hoc risk analysis, the benefit was mainly seen in intermediate-risk, but not low-risk, men (Jones et al. 2011) (Tables 1 and 2).

Table 1 Neoadjuvant or adjuvant hormone therapy plus radiotherapy (EAU Guidelines 2017). For men with locally advanced disease or high-risk patients, the combination of RT with ADT is superior to RT alone followed by deferred ADT on relapse, as shown by phase III RCTs. For intermediate risk, 6 months of ADT is recommended, for high-risk patients, up to 3 years of ADT is recommended. Studies of ADT in combination with RT for PCa
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Table 2 Studies of ADT in combination with or without RT for PCa (EAU Guidelines 2017)
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ADT for Biochemical Recurrence After Treatment with Curative Intent (Surgery/Radiation)

Cure rates for surgery or radiation for localized prostate cancer are depending on primary risk classification; biochemical failure can be observed in up to 30–50% (EAU Guidelines 2017).

The timing as well as the mode of treatment for PSA-only recurrences after RP or RT are still controversial.

Following RP, biochemical recurrence may be defined by two consecutive PSA values of >0.2 ng/mL (Moul 2000).

Following RT, according to the RTOG-ASTRO Phoenix Consensus Conference definition, biochemical recurrence may be defined by any PSA increase >2 ng/mL higher than the PSA nadir value, regardless of the serum concentration of the nadir (Roach 3rd et al. 2006).

Therapeutic options for biochemical recurrence after rad. Prostatectomy include radiotherapy at least to the prostatic bed; androgen deprivation therapy, intermittent androgen deprivation (IAD), as well as observation. Therapeutic options for patients with biochemical progression post radiation include ADT or local procedures such as Salvage Radical Prostatectomy (SRP), cryotherapy, interstitial brachytherapy, and HIFU (Heidenreich et al. 2008; Ahlering et al. 1992; Zincke 1992; Lerner et al. 1995). Patients in the low-risk subgroup typically respond very well to salvage RT with a high probability of PSA being undetectable (Briganti et al. 2014).

Adding ADT to salvage RT has shown benefit in terms of biochemical PFS in retrospective series (Goenka et al. 2012; Choo et al. 2009) and in PFS for “high-risk” tumors (Soto et al. 2012); however, data from prospective randomized trials are missing.

Ongoing trials include the Radiation Therapy Oncology Group RTOG 96-01 comparing RT + placebo vs. a combination of RT + bicalutamide (150 mg daily) in the postoperative setting and the French GETUG 16 trial, comparing salvage EBRT with or without 6 months of ADT (EAU Guidelines 2017).

Recent data from RTOG 9601 suggested both CSS and OS benefits for adding 2 years of bicalutamide to SRT. According to GETUG-AFU 16, also 6 months treatment with gonadotropin-releasing hormone (GnRH) analogue can improve 5-year PFS significantly.

Clinical effectiveness of ADT after curative therapy is still unclear and the published data are inconsistent; a favorable effect was reported for high-risk patients with a short PSA-DT by Boorjian et al. (2011).

Because of the unproven benefit of early ADT for biochemical recurrence, the treatment approach should be individualized based on a risk stratification with patient-specific factors like age, comorbidity, patient preferences, as well as disease-specific factors like Gleason score and PSA-DT (Zumsteg et al. 2015).

According to the recent EAU guideline, early HT should be recommended for patients with a high risk of disease progression with short PSA-DT at relapse (<6–12 months) and/or a high initial Gleason score (>7), and a long life expectancy.

For all other patients, the potential benefits of salvage HT should be balanced against its potential harms EAU Guidelines (2017); this is comparable to the German S3 guideline, which considers ADT for biochemical recurrence for men with a PSA doubling time <3 months and or symptomatic local progression.

First-Line Hormonal Treatment for Metastatic Prostate Cancer

For patients with symptomatic metastatic prostate cancer, ADT is standard of care for the past decades and should be recommended (Pagliarulo et al. 2012; EAU Guidelines 2017).

For symptomatic treatment, ADT is the preferred causal treatment option due to the good response rates in hormone naive prostate carcinomas and the demonstrated prolongation of progression-free survival.

Androgen deprivation therapy in addition has a significant effect on skeletal related events (SRE) and other complications, e.g., obstruction and hematuria.

However, the treatment of hormone-naive PCa noma has changed in the last 5 years based on the presented data from large randomized controlled trials, demonstrating a significant survival benefit for patients with metastasis when a combination of ADT with chemotherapy with docetaxel is given (Gravis et al. 2013; Sweeney et al. 2015; James et al. 2015).

Three trials compared ADT alone as the standard of care with ADT combined with immediate docetaxel (75 mg/sqm, every 3 weeks). Chemotherapy was given within 3 months of ADT initiation. The primary objective in all 3 studies was overall survival.

In the CHAARTED trial, all patients with newly diagnosed M1 Pca disease were included and patients were stratified according to disease volume; high volume being defined as either presence of visceral metastases or four or more bone metastases, with at least one outside the spine and pelvis (Sweeney et al. 2015). In the french GETUG 15 trial, the same inclusion criteria applied (Gravis et al. 2013).

The STAMPEDE is a multi-arm, multi-stage trial in which the reference arm standard of care ADT monotherapy included 1184 patients. One of the experimental arms was docetaxel combined with ADT (n = 593 patients) (James et al. 2015).

Based on these data, upfront docetaxel combined with ADT should be considered as a new standard in men presenting with metastases at first presentation, provided they are fit enough to receive the drug (Vale et al. 2016) (Table 3).

Table 3 Hormonal treatment combined with chemotherapy (EAU Guidelines 2017)
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Men with newly diagnosed metastases represent an inhomogeneous group of patients with a median survival of at least 42 months (James et al. 2015).

Different prognostic factors for survival have been suggested like number and location of bone metastases, presence of visceral metastases, Gleason score, Performance status, and initial PSA alkaline phosphatase but none of these parameters have been validated in a direct comparison (Gravis et al. 2015).

In the Charted trials, the number and location of bone metastases and the presence of visceral lesion were used as prognostic factors (Sweeney et al. 2015).

Prognostic groups can also be separated according to PSA response after ADT. In the SWOG 9346 trial, PSA level 7 months after ADT differentiated 3 prognostic groups, group 1 with a PSA < 0.2 ng/mL had a median survival of 75 months, group 2 with a PSA < 4 ng/mL had a median survival of 44 months, and group 3 with a PSA > 4 ng/mL had a median survival of only 13 months (Hussain et al. 2006).

Androgen Deprivation Combined with Other Agents

Combination with Abiraterone Acetate

A paradigm shift in the treatment of patients with mPCa has also been initiated by the results of 2 major phase-3 clinical trials (STAMPEDE Arm G, LATITUDE): They demonstrated also a significant advantage of ADT in combination with abiraterone/prednisone over ADT alone.

In the two large RCTs STAMPEDE and LATITUDE the addition of abiraterone acetate (1000 mg daily) plus Prednisone (5 mg daily) (AA plus P) to ADT in men with hormone-sensitive metastatic prostate cancer (mHSPC) was studied (Fizazi et al. 2017; James et al. 2017). Primary objective of both trials was an improvement in OS. Both trials showed a significant OS benefit of 38% at 3 years (HR: 0.62).

All secondary objectives such as progression-free survival, time to radiographic progression, time to pain, or time to chemotherapy were in favor of the combination.

Based on these data, upfront docetaxel or abiraterone combined with ADT should be considered as a standard in men presenting with metastases at first presentation, provided they are fit enough to receive these drugs (Table 4).

Table 4 Results from the STAMPEDE arm G and LATITUDE studies (EAU Guidelines 2017)
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Castration Resistent Prostate Cancer (CRPCa)

According to the recent guidelines, CRPCa is defined as serum levels of testosterone <50 ng/dL or 1.7 nmol/L plus either biochemical progression with three consecutive rises in PSA 1 week apart resulting in two 50% increases over the nadir, and a PSA > 2 ng/mL or radiological progression according to the RECIST (Response Evaluation Criteria in Solid Tumors) (EAU guideline 2017).

All clinical trials in mCRPC include patients who maintain castrate levels of testosterone, and so clinical practice should adhere to this principle of continuing ADT when initiating abiraterone, enzalutamide, or chemotherapy (Merseburger et al. 2015).

The European Association of Urology (EAU) guideline clearly states that when castrate-resistant prostate cancer (CRPC) develops, androgen deprivation therapy (ADT) should be continued indefinitely; this recommendation applies to metastatic CRPC (mCRPC) and nonmetastatic CRPC (nmCRPC) EAU Guidelines (2017). Other guidance, such as that from the American Urological Association (AUA) (Cookson et al. 2013) and the National Comprehensive Cancer Network (NCCN) (NCCN 2017), likewise mention the need to maintain ADT when CRPC develops.

Treatment options with proven survival benefit in CRPCa to target the endocrine pathways include Abiraterone and Enzalutamide, nonhormonal therapies like chemotherapy with docetaxel and Cabazitaxel, Vaccine, and Radium-223.

Abiraterone selectively inhibits the enzyme 17 α-hydroxylaze/C17, 20-lyase (CYP17) and thus inhibits androgen biosynthesis (Attard et al. 2005). Abiraterone also has direct activity on reducing the expression of the androgen receptor gene (Soifer et al. 2012).

Therefore, the need to eliminate as many parts of the androgen receptor signaling pathway as possible provides a rationale for combining abiraterone with ADT. Crucially, experimental evidence suggests that the testosterone suppression achieved by abiraterone monotherapy is not sustained in noncastrated men and is overcome by a subsequent 2- to three-fold surge in luteinizing hormone (LH) levels (O’Donnell et al. 2004). Conversely, the addition of abiraterone to backbone ADT results in sustained decreases in testosterone and adrenal steroid concentrations (Ryan et al. 2014). Although the pharmacokinetic study of O’Donnell et al. (2004) assessed a small number of men, it does suggest a need to maintain castrate levels of testosterone with ADT when initiating abiraterone therapy.

This rationale of combining ADT with abiraterone has been used in phase III trials. The efficacy of abiraterone (plus prednisolone) was demonstrated in two pivotal trials in patients with mCRPC; in one study, abiraterone was used before chemotherapy, and in another study, it was used after chemotherapy (Ryan et al. 2010; Fizazi et al. 2012). Importantly, castration levels of testosterone were maintained in both these studies with the continuation of ADT.

Clinical trials of enzalutamide in men with CRPC included the need for castration maintenance with ADT, and these studies have shown that this combination improved OS when used before chemotherapy and after chemotherapy (Scher et al. 2012).

Androgen receptor signaling persists during castration, and several mechanisms may be responsible for this persistence (Merseburger et al. 2015). Addition of androgen receptor blockers to ADT may achieve a more complete androgen blockade (Tables 5 and 6).

Table 5 Randomized phase III controlled trials – first-line treatment of metastatic castration-resistant PCa (EAU Guidelines 2017)
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Table 6 Randomized controlled phase III – second-line trials in metastatic castration-resistant PCa*
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Since quality of life aspects are important, patients on ADT should be counceled regarding the management of side effects.

The british NICE guideline gives recommendation for managing possible adverse effects of hormone therapy (Graham et al. 2014).

Hot Flushes

Offer medroxyprogesterone (20 mg per day), initially for 10 weeks, to manage troublesome hot flushes caused by long-term androgen suppression and evaluate the effect at the end of the treatment period.

Consider cyproterone acetate (50 mg twice a day for 4 weeks) to treat troublesome hot flushes if medroxyprogesterone is not effective or not tolerated.

Tell men that there is no good-quality evidence for the use of complementary therapies to treat troublesome hot flushes.

Sexual Dysfunction

Before starting androgen deprivation therapy, tell men and, if they wish, their partner that long-term androgen deprivation will cause a reduction in libido and possible loss of sexual function.

Advise men, and if they wish, their partner, about the potential loss of ejaculation and fertility associated with long-term androgen deprivation and offer sperm storage.

Ensure that men starting androgen deprivation therapy have access to specialist erectile dysfunction services.

Consider referring men who are having long-term androgen deprivation therapy, and their partners, for psychosexual counseling.

Offer PDE5 inhibitors to men having long-term androgen deprivation therapy who experience loss of erectile function.

If PDE5 inhibitors fail to restore erectile function or are contraindicated, offer a choice of:

  • Intraurethral inserts

  • Penile injections

  • Penile prostheses

  • Vacuum devices

  • Osteoporosis

Do not routinely offer bisphosphonates to prevent osteoporosis in men with prostate cancer having androgen deprivation therapy.

Consider assessing fracture risk in men with prostate cancer who are having androgen deprivation therapy, in line with Osteoporosis

Offer bisphosphonates to men who are having androgen deprivation therapy and have osteoporosis.

Consider denosumab for men who are having androgen deprivation therapy and have osteoporosis if bisphosphonates are contraindicated or not tolerated.

Gynecomastia

For men starting long-term bicalutamide monotherapy (longer than 6 months), offer prophylactic radiotherapy to both breast buds within the first month of treatment. Choose a single fraction of 8 Gy using orthovoltage or electron beam radiotherapy.

If radiotherapy is unsuccessful in preventing gynecomastia, weekly tamoxifen should be considered.

Fatigue

Tell men who are starting androgen deprivation therapy that fatigue is a recognized side effect of this therapy and not necessarily a result of prostate cancer.

Offer men who are starting or having androgen deprivation therapy supervised resistance and aerobic exercise at least twice a week for 12 weeks to reduce fatigue and improve quality of life.