Hypercastration in prostate cancer

Keywords::

• abiraterone
• androgen depedence
• castration-resistant prostate cancer
• enzalutamide
• prostate cancer

Prostate cancer has the highest prevalence among solid tumors in Western countries. In Europe, 382,000 men were diagnosed with prostate cancer and 89,000 men died of the disease in 2008 [1], while one out of 160 living men had received a previous diagnosis of prostate cancer in 2003 [2]. Frustration in the medical community has increased over the past few decades as extensive research has failed to identify any breakthrough biomarker for early diagnosis [3] and screening remains controversial [4], owing to the consistent risk of overtreatment, with its detrimental effects on quality of life and considerable financial burden. If primary treatment fails to eradicate the disease, prostate cancer inexorably progresses to a state which was once defined as ‘hormone-refractory’, and is now referred to as ‘castration-resistant’, which indicates that standard hormonal manipulations, including the use of Luteinizing hormone-releasing hormone analogs and/or antiandrogens such as bicalutamide and flutamide, are no longer effective to control disease progression. It is now clear that prostate cancer that is resistant to castration is actually ‘hormone-driven’ and still potentially sensitive to hormonal manipulations, as shown by the recent, exciting results obtained with novel hormonal agents [5]. In castrated patients, the androgen receptor can be activated via a number of diverse mechanisms, which include crosstalk with other signaling pathways, such as Src, Akt, human epidermal growth factor receptor 2, insulin-like growth factor 1 receptor and IL-6 [6], intratumoral and adrenal steroid biosynthesis [7], amplification and/or mutation of the androgen receptor gene [7]. Selective pressure exerted by hormonal manipulations results in the onset of resistance that progressively develops through four ‘states’, defined by dependance of cancer growth on testosterone and on the activation of the androgen receptor [8]. In the first state (endocrine androgen dependence), testosterone is essential for the activation of the androgen receptor, while in the second state (intracrine androgen dependence), the androgen receptor is stimulated by androgens of intracellular origin, which are synthesized either de novo or from adrenal precursors. The androgen receptor is constitutively activated in the third state (ligand independence or androgen receptor dependence), due to the expression of androgen receptor splice variants and crosstalk with other signal transduction pathways such as those dependent on HER2/neu and Src kinase receptors. In the fourth state (androgen independence and androgen receptor independence), activation of the androgen receptor is not responsible for tumor progression, which can be driven by the antiapoptotic effect caused by hyperexpression of bcl-2 and inactivation of the tumor-suppressor gene p53 [9,10]. At this last point in the course of the disease, any hormonal treatment is likely to be ineffective.

Classification of patients according to these four states could be of great use for definition of the therapeutic strategy, which is currently mainly based on the type of previous therapy administered. Docetaxel was tested and approved in castration-resistant prostate cancer (CRPC) patients, while patients were selected according to whether they had received previous treatment with docetaxel in Phase III trials on two hormonal agents such as abiraterone and enzalutamide [5]. Enzalutamide (MDV 3100) is a nonsteroidal androgen antagonist with an appealing pharmacodynamic profile. Not only does it present a five- to eightfold higher affinity for the androgen receptor with respect to bicalutamide with no partial agonist activity, but it also inhibits translocation of the androgen receptor into the nucleus, thus preventing its binding to DNA [5]. Abiraterone acetate is an oral inhibitor of cytochrome P450 c17 (CYP17), which works by inhibiting steroid biosynthesis at an adrenal and intratumoral level [6]. Androgen can be synthesized by cancer cells either de novo from cholesterol or from adrenal precursors [6]. Of note, homogeneous, intense expression of nuclear androgen receptor in combination with CYP17 tumor expression was correlated with longer time to treatment discontinuation (>4 months) in a subset of 25 patients treated with abiraterone [11]. Similar experiences in larger samples may pave the way for assessing androgen dependence in patients as described before, with important implications in the therapeutic decision-making process.

Even in castrated patients, abiraterone was able to lower both testosterone and dydrotestosterone both in bone marrow aspirate plasma and in blood plasma [11], achieving what we here define as ‘hypercastration’. The potential benefit of early achievement of hypercastration (e.g., in castration-sensitive prostate cancer patients, or in chemotherapy-naive CRPC patients) is of great interest and is being investigated in clinical trials. In this regard, the COU-AA-302 trial showed that the use of abiraterone acetate plus prednisone in asymptomatic or mildly symptomatic patients with metastatic CRPC was associated with a statistically meaningful advantage in radiographic progression-free survival versus placebo plus prednisone [12]. An advantage in overall survival was recorded in favor of the active arm, but it did not satisfy the prespecified statistical boundaries required by the study design. Unfortunately, the COU-AA-302 trial did not assess the effect that postponing docetaxel might have in a population of metastatic CRPC patients [12]. Furthermore, once hypercastration is obtained with abiraterone, it may be beneficial to maintain it after disease progression, in the same fashion as castration is maintained in CRPC patients. Of note, abiraterone is excellently tolerated and it appears feasible to combine it with agents of different classes, including immunotherapy [13], chemotherapy or hormone therapy. Continuation of abiraterone after progression may provide the same advantageous as those provided by targeted drugs in other solid malignancies, such as trastuzumab in breast cancer [14] or bevacizumab in colon cancer [15].

As novel agents showing noncumulative toxicity can be safely combined with other treatments, the paradigm that separates one line of treatment from another on the basis of progression can be progressively abandoned. One intriguing concept is the possibility to abandon the concept of progression as a dichotomous variable, but to measure it instead as a continuous variable in terms of ‘progression velocity’. As upregulation of the CYP17A is a putative mechanism of resistance to abiraterone [6], suspension of abiraterone may accelerate progression and its continuation may slow down disease progression even in patients with progressive disease.

Prostate cancer was the first malignancy to have benefited from continuation of a treatment ineffective alone to control progressive disease. Further studies are required to evaluate whether selected agents may be continued beyond progression, with a careful assessment of the benefits, costs and disadvantages of such an exciting strategy.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.