With a global incidence of 899,102 new cases diagnosed each year causing 258,133 attributable deaths, prostate cancer (PCa) is a leading cause of death from cancer in men worldwide.1

Despite high rates of cure in the majority of men treated with currently available local treatments, up to a third will ultimately develop progression to metastatic disease, which in most men will be characterized initially by increasing PSA levels. For more than 50 years, hormonal therapy with medical or surgical castration has been the mainstay of initial systemic therapy for recurrent and advanced prostate cancer, with luteinizing hormone-releasing hormone (LHRH) analogues that suppress testicular testosterone production being the most commonly used agent in first-line hormone therapy.

However, despite initial treatment efficacy in most men, further cancer progression, as indicated by either increasing PSA levels and/or development of new sites of spread, are detectable within an average of 18 to 24 months.2 When PCa becomes refractory to primary hormonal ablative therapies, treatment options for patients are few, and the resulting life expectancy is limited, with a median survival time on the order of two years.2-4

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Interestingly, it has been long recognized that most men who experience disease progression on primary LHRH therapy will still demonstrate biochemical and/or clinical responses to further secondary hormonal manipulations. In recent years it has become apparent that PCa that recurs during androgen deprivation therapy is not truly refractory to the effects of androgens.

In fact, it now appears that the opposite is true: Using a variety of molecular adaptations, PCa actually becomes hypersensitive to the stimulatory effects of even extremely low levels of androgens and demonstrates persistent signaling-mediated growth through the androgen receptor (AR).5 Today, therefore, rather than speaking of “hormone refractory” PCa, it has been suggested that it is more accurate to speak of cancers that have progressed to the castration-resistant PCa (CRPC) state.

The new biological knowledge obtained over the past decade has provided an understanding of why secondary hormonal therapies remain effective, and has provided new strategies for treating CRPC. Herein, we review the current secondary hormone therapies for CRPC, and introduce several novel treatments that are currently under investigation or expected to become available shortly.

Current therapies

Secondary hormonal manipulation for CRPC Traditional secondary hormonal manipulations include the use of low- and high-dose antiandrogens, antiandrogen withdrawal, glucocorticoids, estrogens, ketoconazole, and aminogluthemide. Lacking definitive evidence of improvement in cancer-specific survival, these second-line treatments consistently demonstrate biochemical and/or clinical benefits in a large portion of CRPC patients. However, therapeutic success is limited, the anticipated treatment duration is short, and except for antiandrogens, the mechanisms of action are primarily nonspecific. Furthermore, each subsequent, serial hormonal is less likely to meet with success.6

Second-line antiandrogens and antiandrogen withdrawal  Several antiandrogen therapy regimens after a failed drug or surgical castration therapy are possible: combined androgen blockade (CAB), antiandrogens alone, or antiandrogen withdrawal. Deferred use of systemic antiandrogens after progression on gonadal androgen suppression has shown a 50% or greater decrease in PSA in 80% of patients with localized disease and 54% of those with metastatic disease.7 Another study of symptomatic CRPC patients indicated a 50% or greater PSA decrease with deferred flutamide in 23% of cases.8

Use of second-line antiandrogen monotherapy, which is often associated with gynecomastia and breast tenderness that can be avoided with prophylactic breast irradiation, can lead to a PSA response of 50% or greater in 4%–50% of patients. The median duration of therapy is between 4.0 and 11.0 months.9-14 In particular, 20% to 40% of the patients treated with high doses (150 to 200 mg) of bicalutamide have PSA decreases of 50% or greater, with most responses seen in those who received prior flutamide therapy.2 A similar result was reported for nilutamide, with a PSA decrease 50% or greater in 29% of patients.12

After prolonged use, antiandrogens often begin to develop partial AR agonist activity. This biological effect is used for the therapeutic maneuver of antiandrogen withdrawal syndrome (AAWD). The effect describes a PSA decline after discontinuation of antiandrogens with or without subjective or objective symptomatic improvement.15-17

AAWD is associated with a PSA decline of 50% or greater in 10%-15% of subjects, with responses lasting a median of six months.17, 18 However, it must be acknowledged that objective responses in these patients, despite a significant decrease in the PSA value, are very low.18

Non-specific steroid hormone manipulation Ketoconazole and aminogluthemide have also been further treatment options for CRPC. Both drugs inhibit the first step in the steroid biosynthesis from cholesterol to pregnenolone with resulting impact on all downstream products of the steroid biosynthesis pathways, including mineralocorticoids, glycocorticoids, testosterone, and estrogens.

Ketoconazole—originally approved as an anti-fungal agent and given for PCa in higher doses up to 1200 mg/day and in combination with hydrocortisone—interacts with further steps of the steroid biosynthesis pathway as well. For the most part, ketoconzole has supplanted the use of aminogluthemide.6

The efficacy of ketoconazole has been demonstrated in 30%-60% of CRPC cases, with a median response duration of about seven months.6, 18-20 Ketoconazole has been shown to induce a 50% or greater decrease in PSA in 32% of the cases after AAWD.18 The administration of ketoconazole, however, is often associated with moderate-to-severe adverse effects, the most dangerous being liver toxicity. Furthermore, ketokonazole has been associated with lethargy, skin rash, and diarrhea and with adverse drug interactions through its inhibition of the p450 cytochromes in the liver.

Treatment with glucocortocoids Several kinds of glucocorticoids have been used in the past for secondary hormonal manipulations. In general, the treatment duration is short, with a median of only two months. Studies have reported PSA response rates of 50% or greater in 20% of patients for prednisone or hydrocortisone, and in up to 60% for dexamethasone.21-23 The biological effects that underlie these clinical observations are not well understood. Despite their short treatment duration, there is additional evidence to support the palliative effects of corticoids in terms of pain control and preventing nausea and vomiting.

Estrogen-based treatment Diethylstilbestrol (DES) is thought to be able to reduce testosterone production by inhibiting hypothalamic LHRH and pituitary LH production, and it has been shown to be active against prostate cancer cell lines.24 A number of studies have reported results using DES. For the most part, it is able to decrease the PSA by 50% or more in 20%-40% of patients, with a median treatment duration of four months.

This reasonable therapeutic success is often accompanied by a substantially increased risk of cardiac and vascular adverse effects such as myocardial infarction, stroke, and pulmonary embolism.2, 6 Because of these adverse effects, the use of a concomitant anticoagulative therapy such as warfarin or aspirin is generally recommended.6 Use of estrogen therapy in the form of DES, however, has been reported to be associated with reduced rates of bone resorption and osteoporosis, and possible benefits on cognitive function.25