Abiraterone acetate, a first-in-class CYP17 inhibitor, establishes a new treatment paradigm in castration-resistant prostate cancer

Keywords::

• abiraterone
• androgen ablation therapy
• androgen-deprivation therapy
• androgen receptor
• castration-resistant prostate cancer
• combination therapy
• CYP17
• drug resistance
• MDV3100
• prostate cancer

Androgen-deprivation therapy (ADT) has been the standard treatment for advanced and metastatic prostate adenocarcinoma for the past seven decades [1]. However, clinical resistance to ADT eventually emerges and leads to a poor clinical outcome [2]. While successful second-line hormone manipulations with agents such as first-generation antiandrogens (flutamide, bicalutamide and nilutamide) and the antifungal ketoconazole (that also has activity as an androgen synthesis inhibitor) are still possible, these responses are usually short lived and associated with significant toxicities [3]. Chemotherapy is frequently used in this setting (with less than ideal responses) [4], under the inaccurate assumption that the disease is, at this point, ‘hormone-refractory’ or ‘androgen-independent’, terms mistakenly used frequently throughout the literature. However, the re-expression of PSA [5], an androgen receptor (AR)-regulated gene, in prostate cancers that have progressed after ADT, and its subsequent decline after treatment with second-line hormonal therapies has demonstrated that the AR pathway is still active at the molecular level. These data demonstrate that the tumor is not necessarily ‘androgen-independent’ [6]. Instead, the term ‘castration-resistant prostate cancer’ (CRPC) is more appropriate [1].

Several mechanisms have been proposed to explain the persistence of AR signaling in CRPC. Evidence has accumulated in recent years for each of these mechanisms, suggesting that these are not mutually exclusive and that substantial heterogeneity is present [2]. It is becoming clear, for example, that ADT causes growth arrest, but does not induce significant apoptosis in prostate cancer cells [7]. This provides them time to adapt to low androgen levels and, eventually, restart proliferating despite suppressed circulating peripheral testosterone levels [8]. More recent in vitro evidence had shown that a subset of prostate cancer cells that survive androgen-depleted conditions express increased levels of stem cell markers and are able to repopulate the tumor, possibly through adaptive AR pathway changes [9]. These adaptive changes include AR overexpression [6,10] or gain-of-function mutations [2,4] that increase receptor sensitivity to circulating androgens. Alternatively, these mutations can also allow AR to be activated by noncanonical ligands [2], such as other steroids (e.g., progesterone) [1], or even by agents initially used as antiandrogens in the same patient (e.g., flutamide and bicalutamide). The latter phenomenon, also known as the ‘antagonist-to-agonist’ conversion of these first generation antiandrogens, explains the ‘antiandrogen withdrawal’ effect (i.e., the decline in PSA manifested in ∼25% of patients following the discontinuation of these drugs after clinical progression) [1,10]. Furthermore, the sensitivity of AR to its ligand(s) can also be modulated or enhanced by changes in the activity of coactivators and/or corepressors that play important roles in AR transcriptional activity [1]. In fact, changes in the coactivator-to-corepressor ratio have been proposed as another possible explanation for the ‘antagonist-to-agonist’ conversion of antiandrogens [4].

Another crucial mechanism of prostate cancer progression after ADT is based on the fact that, while gonadotropin-releasing hormone analogs suppress gonadal synthesis of testosterone, they do not affect adrenal production of androgen precursors (dehydroepiandrosterone and androstenedione) that can then become available to the prostate cancer tissue and serve as precursors to testosterone [11]. The importance of these androgen precursors is very high, as the circulating concentrations of dehydroepiandrosterone are much higher than those of testosterone in healthy males. During ADT, serum testosterone and dihydrotestosterone (DHT) levels decrease by >90%, while intraprostatic testosterone and DHT levels decrease by only 60–70% and have a closer correlation with serum dehydroepiandrosterone levels. Moreover, as reported by Montgomery and colleagues, the intraprostatic concentrations of testosterone were up to fourfold higher in metastatic tissue from CRPC patients (despite castrate levels of testosterone in the serum), compared to primary prostate cancer tissue from untreated eugonadal patients [12]. Taken together, these findings suggest that ADT activates an adaptive response in the prostate cancer tissue, which augments its ability to convert adrenal precursors into testosterone and DHT [13], probably via upregulation of steroidogenic enzymes (e.g., AKR1C3) [14], to a concentration sufficient to promote AR-dependent gene expression [2,6]. Somewhat more controversial is the concept that prostate cancer tissue is able to synthesize testosterone de novo directly from cholesterol [11]. Supporting this theory, some investigators have reported upregulation of the key steroidogenic enzyme CYP17 in prostate cells after ADT [12]. Others, however, have suggested that CYP17 levels in prostate cancer tissue are inadequate for local de novo synthesis of testosterone directly from cholesterol, and implicated adrenal CYP17 as the major source of androgen precursors after ADT [15].

In any case, adrenal androgen precursors are a crucial source of AR ligands after ADT, and attempts to suppress it have been ongoing for several years. Initially, the antifungal agent ketoconazole was used as it has inhibitory activity on several enzymes involved in androgen synthesis, such as CYP17 and CYP11, and can provide brief clinical responses. However, ketoconazole is a weak androgen synthesis inhibitor and causes substantial toxicity [3]. Abiraterone acetate – a newer, more potent and better tolerated CYP17 inhibitor – accomplished a significant overall survival benefit of 3.9 months in a Phase III trial in chemotherapy-refractory CRPC patients [16], leading to its recent approval by the US FDA for the treatment of prostate cancer in this clinical setting. Most importantly, these results provide proof-of-principle that the AR signaling pathway is still quite active in patients with castrate levels of peripheral testosterone and represent a therapeutic opportunity for the development of future combination therapies.

Specifically, the use of abiraterone acetate in combination with gonadotropin-releasing hormone analogs as first-line therapy for prostate cancer could potentially cause more potent upfront androgen depletion within the prostate cancer microenvironment, possibly achieving more substantial apoptosis of prostate cancer cells and denying them the opportunity to undergo adaptive changes, such as the ones mentioned previously, that would lead to the emergence of CRPC. This maximal upfront suppression of intratumoral androgen levels could significantly increase the time to clinical progression and even improve overall survival for patients with locally advanced or even metastatic disease.

Other future directions include the development of additional CYP17 inhibitors. TAK700 (orteronel), currently in Phase III testing in CRPC, was designed to preferentially inhibit the 17,20 lyase activity of CYP17 (which is necessary for androgen synthesis only) as opposed to 17-hydroxylase activity (that is required for both androgen and glucocorticoid synthesis) [17]. As abiraterone blocks both the 17-hydroxylase and 17,20 lyase activities of CYP17, it requires concomitant glucocorticoid supplementation [3,16]. Therefore, TAK700 was designed with the hope of obviating the need for glucocorticoid supplementation, although it remains unclear whether this specificity will be maintained with the higher doses that are required in clinical practice. Another novel agent in clinical development is galeterone (TOK-001 or VN/124-1), which is both a CYP17 inhibitor and an AR antagonist [1]. The results from these clinical trials are eagerly awaited.

While the available results and future expectations for abiraterone and other anti-AR targeted therapies are encouraging, all patients that receive abiraterone under its current indication are expected to eventually progress. This highlights the multiple mechanisms for resistance observed in CRPC. The increased expression of AR mRNA variants, which lack the ligand-binding domain and are constitutively active, provides a likely explanation for the progression seen after an initial response to abiraterone [18,19]. The expression of these variants increases acutely in response to androgen ablation, such as that induced by abiraterone, while it is suppressed by testosterone [19]. It has been reported that the transcriptional activity of these AR variants can be blocked by MDV3100, a high-affinity AR antagonist [20]. This compound was rationally designed using data from a cocrystal structure of bicalutamide bound with mutant AR to create a chemical library that was screened for AR antagonistic activity [10]. In preclinical experiments [10], MDV3100 does not appear (so far) to have an agonistic effect on AR, contrary to the first generation antiandrogens, reportedly because of the impairment of AR translocation and DNA binding produced by this newer drug [1]. Initial clinical data shows that MDV3100 has relatively few side effects [5], which, along with their noncompeting mechanisms of action, could argue in favor of its use in combination with abiraterone. Recent Phase III data demonstrate a 4.8-month overall survival benefit for chemotherapy-refractory patients treated with MDV3100 compared with placebo. However, the best use for MDV3100 is still undetermined. Similarly, its reported ability to block AR variants is yet to be tested in a rigorous clinical setting.

After many years in which new developments were stalled, excellent translational research has finally brought us to an exciting era in the management of prostate cancer by means of rationally designed new drugs. This research has not only provided medications to be added to the armamentarium for CRPC treatment, but most importantly, gave us a deeper understanding of the pathways involved in this disease and the mechanisms of resistance to hormonal therapies. With many of these mechanisms at play, sometimes simultaneously (explaining the variable and short-lived responses seen among different patients), the next logical step seems to be the use of combination regimens with these and other drugs which could potentially increase treatment efficacy. Although doing this while avoiding dose-limiting toxicity has been challenging in the past, the higher activity and the nonoverlapping side-effect profiles of these new-generation drugs increase the likelihood of success.

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.