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Androgen Deprivation Therapy: Drugs and Side Effects

Androgen deprivation therapy (ADT) is a treatment option for advanced prostate cancer in the following situations:

• Metastatic prostate cancer
• Biochemical progression of prostate cancer with no detectable metastases and a PSA doubling time below three months
• Adjuvant therapy of advanced prostate cancer after radical prostatectomy or radiation therapy
• Conservative treatment of locally advanced prostate cancer with LUTS
• Lowering prostate volume before brachytherapy

Classification of Drugs for Androgen Deprivation Therapy

• Classic androgen receptor antagonists: nonsteroidal drugs are bicalutamide and flutamide. Cyproterone acetate is a classic steroidal antiandrogen with a progestational effect, which causes additional central inhibition of the testosterone concentration.
• GnRH agonists: Buserelin, Goserelin, Histrelin, Leuprorelin, and Triptorelin
• GnRH antagonists: degarelix and relugolix
• Estrogens: Fosfestrol
• Androgen synthesis inhibitors: Abiraterone.
• Modern androgen receptor antagonists: Enzalutamide, Apalutamide, Darolutamide.

Principles of Androgen Deprivation Therapy

The individual therapy options are applied sequentially or in combination depending on disease progression and response [fig. androgen deprivation therapy of prostate cancer]. Please see also the section on metastatic prostate cancer for details.

Androgen deprivation therapy (ADT) of advanced prostate cancer: 1: A maximum of 2--4 visible bone metastases (depending on the study) in conventional imaging. 2: Options are orchiectomy, GnRH analogs, or GnRH antagonists. 3: At least two of the following risk factors: Gleason score ≥8, at least 3 bone metastases, or evidence of visceral metastases. 4: At least 4 bone metastases (including at least one beyond the pelvis or spine) or the presence of visceral metastases. 6: M0 CRPC with a PSA doubling time of less than ten months. 7: The order of the sequence is not defined.

General Side Effects of Androgen Deprivation Therapy

Androgen Deprivation Therapy (ADT) leads to significant side effects, especially in long-term use. Androgen receptor antagonists do not lower the testosterone concentration and cause fewer side effects (except gynecomastia) compared to orchiectomy or GnRH modulators. General measures for the prevention of the side effects listed below are increasing physical activity, striving for a normal body weight, eating a vitamin-rich, healthy diet, and not smoking (Nguyen et al., 2015).

Hot flashes:

Hot flashes are very common; treatment options are (off-label use) Clonidine, Cyproteronacetat, Venlafaxine, or Paroxetine (Loprinzi et al., 2004).

Erectile dysfunction and loss of libido:

ADT leads to severe erectile dysfunction (over 80%) and loss of libido (over 95%). Effective treatment of libido loss is not possible, but the psychological burden of sexual dysfunction is low. Therapeutic options against erectile dysfunction (PDE5 inhibitors or SKAT) are not often requested. Long-term ADT leads to reductions in both penile and testicular size.

Gynecomastia and mastodynia:

Gynecomastia is a very common side effect of androgen receptor antagonists. When bicalutamide 150 mg is administered alone, the risk for gynecomastia is well over 70% after one year. The prophylactic single irradiation with 12–18 Gy of the mammary glands before treatment significantly lowers the risk to 30–50 %. The risk of gynecomastia for combined hormone therapy is lower and amounts to about 20%. Gynecomastia is rare if GnRH modulators are used alone.

The prophylactic administration of tamoxifen (off-label) is more potent than the irradiation to reduce the frequency of gynecomastia (10% vs. 30–50%). The dosage of tamoxifen is 20 mg/d. The effect of tamoxifen does not appear to affect hormone therapy and the biological behavior of prostate cancer (Fradet et al., 2007). Another therapy option is subcutaneous mastectomy.

Cognitive function and mood disorders:

Cognitive function is disturbed by ADT. Furthermore, decreased libido, fatigue, and episodes of depression (relative risk RR of 8) are more common.

Metabolic changes:

Androgen deprivation leads to a loss of muscle mass and increase in body fat, after a year the body weight has increased on average 2–4%. The risk of metabolic syndrome and type II diabetes is also significantly increased.

Cardiovascular risks:

Androgen deprivation leads to an increase in cardiovascular diseases (the relative risk in brackets): CHD (RR 1.2), myocardial infarction (RR 1.1), life-threatening cardiac arrhythmias, or sudden cardiac death (RR 1.16). Cardiovascular mortality increases by 1–6% compared to the placebo group, depending on the study and follow-up period (Levine et al., 2010).

Osteoporosis and fractures:

Osteoporosis is a common complication of long-term ADT with GnRH modulators or castration (Diamond et al., 2004b). The administration of androgen receptor blockers (e.g., Bicalutamide) is not associated with osteoporosis (SmithMR et al, 2004). The fracture rate among men surviving at least 5 years is 19% with ADT versus 13% without ADT. All patients with a long-term prognosis should receive prophylactic vitamin D (800–1000 IU) and calcium (1000 mg). Additional treatment options for osteoporosis with increased fracture risk include bisphosphonates or denosumab.

Anemia:

Normochromic normocytic anemia develops in patients with long-term ADT, which responds well to erythropoietin (Choo et al., 2005).

References

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  Deutsche Version: Antiandrogene Therapie