Targeting the Adrenal Gland in Castration-Resistant Prostate Cancer: A Case for Orteronel, a Selective CYP-17 17,20-Lyase Inhibitor
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- Zhu, H. & Garcia, J.A. Curr Oncol Rep (2013) 15: 105. doi:10.1007/s11912-013-0300-1
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Androgen and the androgen receptor (AR) pathway remain the key targets for emerging new therapies against castration-resistant prostate cancer (CRPC). Adrenal androgens and intratumoral testosterone production appear to be sufficient to activate AR in the castration-resistant setting. This process re-engages AR and allows it to continue to be the primary target responsible for prostate cancer progression. Adrenal androgen production can be blocked by inhibiting cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17), a key enzyme for androgen synthesis in adrenal glands and peripheral tissues. Therapeutic CYP17 inhibition by ketoconazole or by the recently approved adrenal inhibitor abiraterone acetate is the only available choice to target this pathway in CRPC. A new CYP17 inhibitor, with more selective inhibition of 17,20-lyase over 17α-hydroxylase, orteronel (TAK-700), is currently undergoing phase III clinical trials in pre- and postchemotherapy CRPC. In a completed phase II trial in CRPC patients, orteronel demonstrated its efficacy by lowering the levels of circulating androgens, reducing prostate-specific antigen (PSA) levels, and decreasing the levels of circulating tumor cells. Ongoing studies evaluating orteronel in CRPC will further define its safety and role in the management of this disease.
KeywordsCastration-resistant prostate cancerOrteronelTAK-700CYP17 inhibitorHormonal therapyAndrogen-deprivation therapy
Prostate cancer is the commonest noncutaneous malignancy and the second most frequent cause of cancer-related mortality in men in the USA. The National Cancer Institute estimated that in 2012 there would be 241,740 new cases of and 28,170 deaths from prostate cancer.
Since Huggins  made the observation over 70 years ago that the growth and survival of prostate cancer are dependent on androgens, androgen-deprivation therapy (ADT) has been the mainstay of treatment of metastatic prostate cancer. For localized or locally advanced disease, ADT is frequently combined with prostatectomy and radiotherapy in patients at high risk of recurrence. For metastatic prostate cancer, ADT is the first-line treatment and the backbone of any combination therapy. ADT is frequently accomplished through bilateral orchiectomy, or with gonadotropin-releasing hormone analogs (e.g., leuprolide, goserelin), which typically results in greater than 90 % reduction of serum testosterone level, and reach the castrate level (conventionally described as a testosterone level less than 50 ng/dL). Although most men undergoing ADT have an initial response to therapy, eventually all men will develop castration-resistant prostate cancer (CRPC) [2, 3]. Disease progression is manifested by increased serum prostate-specific antigen (PSA) level, radiographic progression, or exacerbation of cancer-related symptoms. Systemic treatment options for CRPC often include second-line hormonal maneuvers, administration of sipuleucel-T, docetaxel-based chemotherapy, or supportive care.
Improved understanding of the signaling pathway of androgen receptor (AR) and its role in the progression of CRPC led to the development of several new therapies that showed promising clinical outcomes in the postchemotherapy setting. This review will briefly summarize several established mechanisms by which prostate cancer circumvents castration, as well as some promising agents that target these mechanisms. The focus of this review is a category of agents that inhibit cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17), a key enzyme in adrenal androgen synthesis. For many years, a nonselective CYP17 inhibitor, ketoconazole, has been clinically prescribed to treat CRPC. A more potent selective CYP 17 inhibitor, abiraterone acetate, was recently approved by the US Food and Drug Administration (FDA) for treatment of docetaxel-refractory metastatic CRPC on the basis of its published phase III clinical trial results (NCT00638690) [4•]. Orteronel (TAK-700) is a novel CYP17 inhibitor currently undergoing phase III clinical trials for treatment of CRPC at various stages of the disease.
Androgen and AR Signaling in Prostate Cancer
Prostate growth and differentiation is stimulated by androgen acting through the AR in the prostate cells. In contrast, androgen deprivation induces apoptosis of the prostate cells . The dependence of prostate cells on AR signaling persists after the neoplastic transformation [1, 5], and thus forms the primary rationale of the current ADT for prostate cancer.
The circulating androgen levels are predominately regulated through the hypothalamic–pituitary–adrenal/gonadal axis. Most androgens are synthesized in the testes and the adrenal glands. In men, 90-95 % of circulating androgens are released from the testes in the form of testosterone [6, 7]. Adrenal glands generate the remaining androgens in the form of androstenedione (AED) and dehydroepiandrosterone (DHEA), which are enzymatically converted to testosterone and dihydrotestosterone (DHT) in the prostate and peripheral tissues. When free testosterone enters prostate cells, nearly 90 % is converted to DHT by the enzyme 5α-reductase. DHT is the more active androgen hormone, with a fivefold higher affinity for AR.
AR belongs to the steroid hormone receptor family of ligand-activated nuclear transcription factors [8, 9]. It is composed of an amino-terminal activating domain, a carboxy-terminal ligand-binding domain (LBD), and a DNA-binding domain in the mid region. The inactive AR is primarily found in cytoplasm bound to heat shock proteins . The binding of testosterone and DHT to the LBD of AR triggers the dissociation of heat shock proteins from AR and activates AR. Activated AR undergoes dimerization and phosphorylation and translocates to the nucleus . In the nucleus, AR dimer binds to the androgen response element , which in turn activates or suppresses the target gene-mediated cell proliferation, differentiation, apoptosis, and metabolism in the prostate and many other tissues. The production of PSA in the prostate is also activated by AR, making it a conventional surrogate for disease progression in PSA-producing prostate cancer .
Development of CRPC
Intracrine production of androgen/testosterone. Under the circumstances of castrate-level circulating testosterone, prostate cells can convert the adrenal androgens such as DHEA and AED to DHT [13, 14]. A prostate tissue androgen study in patients who underwent ADT recorded high levels of testosterone and DHT that were sufficient to activate AR [7, 15, 16]. Intraprostatic conversion of adrenal steroids into testosterone and DHT seemed to play a major role in this mechanism [17–19]. Steroidogenesis in tissues other than the testes or adrenal glands also provides CRPC with a growth advantage. De novo androgen synthesis was demonstrated in an LNCaP xenograft mouse model, which suggested prostate cancer cells possess steroidogenic properties, thus allowing their survival in an androgen-depleted environment .
The tissue androgen studies have provoked strong interest in developing new drugs to further decrease the adrenal androgen level as well as local androgen synthesis within prostate cancer. CYP17, a key enzyme in adrenal androgen synthesis, has been the target of many of those new drugs [21, 22]. The role of CYP 17 in androgen synthesis will be elaborated in this review.
AR upregulation. Prostate cancer may survive ADT by increasing its sensitivity to castrate level of androgens. This goal is achieved by increasing AR expression, stability, and nuclear localization [23–25]. Amplified AR gene was detected in 30 % of tumors that developed androgen resistance after androgen ablation therapy, whereas none of the primary tumors from the same patients before androgen ablation had AR gene amplification [23, 24]. Increased AR sensitivity as a consequence of upregulated AR can potentially respond to more intense ADT with further lower androgen levels, or alternatively a combination of ADT and direct AR blockage [23, 26].
Promiscuous AR. This group of mechanisms allows AR to be activated by ligands other than androgen, or even completely independently of any ligands . Gain-of-function mutations of AR allow AR to interact with a broadened spectrum of ligands. For instance, the T877A mutation in the LBD of AR in prostate cancer, a fairly common somatic mutation isolated in metastatic CRPC, allows the mutant AR to be activated by progestins, estrogens, and the antiandrogen flutamide [27, 28]. As a result, the malignant cells can continue to proliferate and avoid apoptosis by using other circulating steroid hormones as a substitute when the level of androgens is low . Prostate cancer harboring gain-of-function mutations will likely develop ADT resistance rapidly, and theoretically will be insensitive to second-line hormonal therapy.
Alternative AR activation. Mutant AR may also gain the ability to be activated by other extracellular peptide signaling, such as growth factors and cytokines [29–35]. Mutations that modify the intracellular kinase activity have a significant effect on AR activity. For instance, phosphatase and tensin homolog mutations with increased phosphatidylinositol 3-kinase/Akt activity are well documented in prostate cancer [36–38]. Another example is that MET receptor tyrosine kinase overexpression was shown to be commoner in metastatic sites than in primary prostate cancer samples . The development of resistance as the consequence of alternative activation of the AR signaling pathway could be the treatment target of receptor tyrosine kinase inhibitors and phosphatidylinositol 3-kinase/Akt inhibitors. Cabozantinib (XL-184) is a small-molecule inhibitor of multiple receptor tyrosine kinases, including RET, MET, and vascular endothelial growth factor receptor 2. Its antitumor activity was observed among several tumor types, including prostate cancer [40•].
In summary, somatic AR mutations have been established to be the driving force in the development and progression of prostate cancer [41, 42]. Metastatic prostate cancer harbors increased incidence of somatic AR mutation in comparison with primary prostate cancer [28, 42–46]. Patients with mutant ARs in their tumors were shown to exhibit a rapid failure of ADT; whereas men without AR mutations showed a prolonged response to hormonal therapy . Conversely, androgen deprivation constantly provides selective pressure targeting the androgen signaling pathway, and nurtures clonal amplification of androgen-independent tumor cells [28, 46–48]. Phenotypic transition to CRPC is an inevitable consequence following hormonal therapy. Understanding the dominant mechanism(s) of individuals who have developed an ADT-resistant transition will provide guidance for choosing the next line of therapy, which is the ultimate approach to individualized cancer treatment.
CYP17 and CYP17 Inhibitors for Treatment of CRPC
Therapeutic CYP17 inhibition to treat prostate cancer and other androgen-dependent diseases has been envisioned for over 50 years [51–53]. Generally, CYP17 inhibitors have been structurally categorized as steroidal or nonsteroidal. Ketoconazole, a nonsteroidal imidazole antifungal with CYP17 inhibition potential, was initially used clinically off-label as second-line hormonal therapy for prostate cancer following the observation that it caused gynecomastia in male patients [54–57]. Several clinical trials demonstrated the efficacy of high-dose ketoconazole in treating CRPC with a PSA response (decrease of PSA level of more than 50 %) rate in the range of 20–60 % [58–60]. However, ketoconazole has been associated with significant side effects, including hepatotoxicity, gastrointestinal toxicity, and adrenal insufficiency. Furthermore, the inhibition of cytochrome P450 enzymes by ketoconazole raised the problem of potential drug–drug interaction, which makes it a less favorable option for oncologists. The promising response observed with ketoconazole merited the investigation of stronger and more selective CYP17 inhibitors.
Following ketoconazole, several steroidal and nonsteroidal CYP17 inhibitors have been designed and tested. Some of them, being several times more specific and potent, were advanced to clinical trials [22, 61–66, 67•, 68, 69]. Abiraterone acetate (Zytiga®), a highly selective nonsteroidal irreversible CYP17 inhibitor, was demonstrated to be ten times more potent than ketoconazole [70–73]. It recently received FDA approval for the treatment of patients with docetaxel-refractory metastatic CRPC on the basis of an improvement in overall survival associated with abiraterone acetate in a randomized phase III study [4•]. In this study, patients who had previously received docetaxel were randomized in a 2:1 ratio to receive 1,000 mg abiraterone acetate daily and 5 mg prednisone twice daily (779 patients) or placebo and 5 mg prednisone twice daily (398 patients). The primary end point was overall survival; secondary end points included PSA response rate, time to PSA progression, and progression-free survival (PFS). With a median follow-up of 12.8 months, treatment with abiraterone acetate resulted in improved overall survival (14.8 vs. 10.9 months for placebo, P < 0.001), PSA response rate (29 % vs. 6 %, P < 0.001), time to PSA progression (10.2 vs. 6.6 months, P < 0.001), and PFS (5.6 vs 3.6 months, P < 0.001) [4•]. Two other phase III trials comparing abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naïve metastatic CRPC patients and asymptomatic or mildly symptomatic metastatic CRPC patients are in the data analysis stage. The results are expected in the coming year.
Orteronel (TAK-700) and Ongoing Trials
Orteronel is a reversible nonsteroidal imidazole CYP17 inhibitor with preferential inhibition of 17,20-lyase over 17α-hydroxylase activity, which downregulates androgenic steroid production in vitro and in vivo [65, 69]. Selective inhibition of 17,20-lyase activity may in theory reduce the need for corticosteroid supplementation, as secondary mineralocorticoid excess induced by CYP17 inhibition may be more dependent on 17α-hydroxylase , which leads to an improved toxicity profile and fewer treatment-emergent adverse events. The initial results of a phase I/II dose-escalation study to establish the safety and efficacy of orteronel in chemotherapy-naïve metastatic CRPC patients have been published (NCT00569153) [66, 67•]. Early data suggested that orteronel has a response profile comparable to that of abiraterone acetate. In the phase II portion of the study, patients received 300 mg orteronel twice daily, 400 mg orteronel twice daily plus 5 mg prednisone twice daily, 600 mg orteronel twice daily plus 5 mg prednisone twice daily, or 600 mg orteronel daily. The published preliminary data showed all doses appeared active and were well tolerated. The PSA response rate at 12 weeks was observed in 63, 52, 41, and 62 % of patients in the cohorts receiving 300 mg orteronel twice daily, 400 mg orteronel twice daily with prednisone, 600 mg orteronel twice daily with prednisone, and 600 mg orteronel daily, respectively. Treatment with orteronel also has an impact on the levels of circulating tumor cells. The mean number of circulating tumor cells of patients in the trial decreased from 16.6 (per 7.5 mL blood) at the baseline to 3.9 at 12 weeks [67•]. In spite of more selective inhibition of 17,20-lyase over 17-α hydroxylase activity, orteronel had side effects similar to those reported with abiraterone acetate. The challenge will be to elucidate how orteronel distinguishes itself from the already well-established agent abiraterone acetate.
An ongoing phase III, randomized, double-blind, multicenter trial comparing orteronel plus prednisone versus placebo plus prednisone in patients with metastatic CRPC that had progressed during or following docetaxel-based chemotherapy is expected to be completed by the end of 2013 (NCT01193257). Approximately 1,083 patients will be enrolled in this study, and will be randomized to the treatment arm and the placebo arm in a 2:1 ratio. The treatment arm patients will receiving 400 mg orteronel orally twice daily, with concomitant 5 mg prednisone twice daily; the placebo arm patients will receive placebo with 5 mg prednisone twice daily. The primary outcome measure is overall survival; the secondary outcome measures are PSA response, pain improvement, and overall radiographic PFS. Similarly, a study evaluating the activity of orteronel in the prechemotherapy CRPC setting is under way. (NCT01193244).
Other trials evaluating the activity and safety of orteronel in combination with ADT and radiotherapy (NCT01546987) and docetaxel chemotherapy (NCT01084655) are under way.
A century of cancer research has started to pay off during the past decade with a booming emergence of novel targeted agents. Specifically in prostate cancer treatment, more drugs have been approved by the US FDA in the past 3 years than in the prior two decades. A better understanding of the pathogenesis of CRPC has been essential to these recent advances. Today, oncologists are armed with multiple cutting-edge weapons against CRPC, including second-line hormonal maneuvers, immunotherapy, cytotoxic therapy, and bone-targeted therapies . In addition to orteronel, there are several other new drugs on the horizon: enzalutamide (MDV3100) is a novel AR signaling inhibitor which demonstrated a significant benefit among postchemotherapy CRPC patients in the phase III AFFIRM study [75, 76•, 77•] and was recently approved for use by the FDA; galeterone (TOK-001), a novel dual inhibitor of CYP17 and AR, has completed phase I testing in men with chemotherapy-naïve CRPC (NCT00959959) [65, 68].
Selected clinical trials evaluating combination therapy with cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17) inhibitors
Abiraterone acetate/prednisone + enzalutamide
CYP17 inhibitor + AR signaling inhibitor
Sipuleucel-T + abiraterone acetate/prednisone concurrently vs. sipuleucel-T followed by abiraterone acetate/prednisone
Immunotherapy + CYP17 inhibitor. Concurrent vs sequential
Abiraterone acetate + cabozantinib
CYP17 inhibitor + receptor tyrosine kinase inhibitor
Abiraterone acetate/prednisone + veliparib
CYP17 inhibitor + PARP inhibitor
Abiraterone acetate/prednisone + placebo vs abiraterone acetate/prednisone + GDC-0980 vs abiraterone acetate/prednisone + GDC-0068
CYP17 inhibitor + PI3K–Akt–mTOR inhibitors
Abiraterone acetate/prednisone + BEZ235, abiraterone acetate/prednisone + BKM120
CYP17 inhibitor + PI3K–Akt–mTOR inhibitors
Abiraterone acetate/prednisone + cabazitaxel
CYP17 inhibitor + cytotoxic therapy
Abiraterone acetate/prednisone + AMG 386
CYP17 inhibitor + angiogenesis inhibitor
Orteronel/prednisone + docetaxel
CYP17 inhibitor + cytotoxic therapy
Another important issue that remains unanswered today is to determine the most logical sequence of treatment. Multiple other aspects should also be taken into consideration when making treatment selection in the castration-resistant setting; these include the presence or absence of clinical symptoms, the time and pace of radiographic progression, functional status, accessibility to health care, and the financial impact on both the individual and the entire community. The management of CRPC has indeed become quite expensive if one simply adds the price of sipuleucel-T followed by chemotherapy followed by abiraterone acetate and enzalutamide therapy. With our current advances in cancer research, it is hoped that tumor profiling at the genomic, transcriptomic, and proteomic level will enable us to categorize the aggressiveness of the tumor and predict its responsiveness to therapies. Tumor-profiling-guided therapy is optimistically anticipated to make its debut in clinical research in the coming decade.
H. Zhu: none; J.A. Garcia: consultant to J&J and Astellas and speakers’ bureaus for J&J.