Abiraterone and other novel androgen-directed strategies for the treatment of prostate cancer: a new era of hormonal therapies is born

Abstract

The number of life-prolonging therapies proven effective in the treatment of metastatic castrate-resistant prostate cancer (CRPC) has been limited until recently. In the past 2 years several such therapies have come to market. In 2010, the autologous immunotherapy sipuleucel-T and the next-generation taxane cabazitaxel were approved in this setting. However, abundant evidence has shown that CRPC growth continues to be driven through androgen-dependent signaling. Both of these drugs fail to take advantage of this targetable oncogenic pathway. Potent specific inhibitors of cytochrome P450-17 have been engineered with the aim of suppressing androgen synthesis beyond that seen with the luteinizing hormone-releasing hormone agonists/antagonists. Abiraterone acetate was developed by rational design based on a pregnenolone parent structure. Its approval by the US Food and Drug Administration (FDA) was granted in 2011 based on phase III data demonstrating an overall survival advantage compared with placebo. More recently, other drugs that act along the androgen signaling pathway, such as orteronel (TAK-700), galeterone (TOK-001), enzalutamide (MDV3100) and ARN-509, have shown promise in clinical trials. Some of these are expected to gain FDA approval in the near future. Here, we review abiraterone and other novel androgen-directed therapeutic strategies for the management of advanced prostate cancer.

Keywords

abiraterone androgen androgen receptor enzalutamide galeterone orteronel prostate cancer

Introduction

More than 70 years have passed since it was first demonstrated that castration could lead to significant remissions in prostate cancer [Huggins et al. 1941]. Since then, targeting of the androgen–androgen receptor (AR) signaling pathway either by blocking androgen synthesis or blocking androgenic effects has been standard of care for men with advanced prostate cancer [Hellerstedt and Pienta, 2002; Kohli and Tindall, 2010]. Until recently, the mainstay of therapy has focused on blocking testicular synthesis of androgens with luteinizing hormone releasing hormone (LHRH) agonists or antagonists. However, all men on LHRH agents will eventually progress. At that time they are termed as having castration-resistant prostate cancer (CRPC). This article will review abiraterone, as well as several novel androgen-directed agents currently in development for use in the treatment of CRPC.

Until recently, therapies that have been shown to be life prolonging in the CRPC setting have been limited to docetaxel chemotherapy [Berthold et al. 2008]. In 2010, two new therapies were US Food and Drug Administration (FDA) approved for patients with advanced CRPC, the autologous immunotherapy sipuleucel-T and the next-generation taxane cabazitaxel [Kantoff et al. 2010; de Bono et al. 2010]. Sipuleucel-T is currently indicated as first-line therapy for patients who are asymptomatic to minimally symptomatic, and cabazitaxel for those who have progressed on docetaxel. Abiraterone was approved for use in the postdocetaxel setting in 2011. It provides men with CRPC a novel means of targeting the androgen–AR pathway.

Traditionally, patients who have shown signs of progression while on LHRH agonists/antagonists were thought to be ‘androgen insensitive’ or ‘hormone refractory’. More recently, it has been demonstrated that androgen-responsive genes continue to be expressed in men that were thought to be androgen insensitive. This implies that the AR signaling pathway continues to drive prostate cancer growth in the majority of patients [Holzbeierlein et al. 2004; Mohler, 2008; Attard et al. 2009a]. The means by which tumors continue to grow despite suppression of testicular androgen is through a variety of mechanisms: increased extragonadal (adrenal, intratumoral and prostatic) androgen synthesis via upregulation of cytochrome P450-17 (CYP17), upregulation of the AR (either by gene amplification or by protein overexpression), activation of AR by other pathways, AR coactivator expression and AR splice variants that may be constitutively active and ligand independent [Mohler, 2008; Stanbrough et al. 2006; Montgomery et al. 2008; Buchanan et al 2001; Xin et al. 2006; Feldman and Feldman, 2001; Nacusi and Tindall, 2009; Hu et al. 2009].

These observations have led to renewed interest in the development of agents that target the androgen–AR pathway in the metastatic CRPC window. Conceptually, these agents target the androgen–AR pathway at the prereceptor, receptor or postreceptor ligand binding level (Figure 1). Abiraterone acetate is the first in a new generation of rationally designed drugs that targets this pathway. Abiraterone functions by further suppressing androgen production above that seen with the LHRH agonists/antagonists alone; inhibiting the androgen–AR pathway at the prereceptor ligand binding level through extragonadal androgen synthesis inhibition. Orteronel (TAK-700), similar to abiraterone, also exerts its effect solely at the prereceptor binding level by suppressing extragonadal androgens. Other agents currently in development exert their effect at multiple levels. Drugs such as enzalutamide (MDV3100) and ARN-509 work at the receptor ligand and postreceptor ligand level, while galeterone (TOK-001) works at the prereceptor ligand and receptor ligand binding levels [Ryan and Tindall, 2011; Vasaitis et al. 2011].

Figure 1.

Drug targets involving the androgen–androgen receptor pathway.

Abiraterone

Background

Increased extragonadal androgen synthesis and upregulation of the AR in patients with CRPC provide a rational basis for further androgen synthesis inhibition through blockade of CYP17, the key family of enzymes responsible for adrenal and intratumoral androgen synthesis from pregnenolone. It has also been shown that up to 25% of men treated with LHRH agents will have breakthrough testosterone levels in the noncastrate range (>50 ng/dl), providing further incentive to develop drugs that more potently block androgen synthesis through a different mechanism than LHRH agonism/antagonism [Morote et al. 2009].

The azole antifungal, ketoconazole, provided the first evidence that more complete androgen suppression can lead to desirable clinical outcomes in the CRPC setting. In a phase III trial evaluating the efficacy of ketoconazole plus antiandrogen withdrawal (AAWD) versus AAWD alone, it was demonstrated that the ketoconazole group had a superior objective response rate (20% versus 2%; p = 0.02) compared with the control arm. Additionally, that trial showed a prostate-specific antigen (PSA) decline of at least 50% in 27% of the ketoconazole group versus 11% in the AAWD alone arm (p = 0.0002). However, there was no median overall survival (OS) benefit observed [Small et al. 2004]. Ketoconazole exhibits its antitumor activity through CYP17 inhibition, a class of enzymes key to adrenal steroid synthesis. It additionally inhibits 11β-hydroxylation and cholesterol side chain cleavage to pregnenolone (Figure 2). This lack of specificity for the CYP17 family of enzymes unfortunately leads to significant toxicities (e.g. hepatotoxicity, gastrointestinal toxicity and adrenal insufficiency) [Vasaitis et al. 2011].

Figure 2.

Steroid/androgen synthesis pathway and the sites of inhibition of ketoconazole (keto), abiraterone (abi), TAK-700, TOK-001 and the 5-α-reductase inhibitors (5α-RIs). A, androgen pathway; ACTH, adrenocorticotropic hormone; CYP17, cytochrome P450-17; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; G, glucocorticoid pathway; M, mineralocorticoid pathway.

Building on the efficacy of ketoconazole, abiraterone was developed at the Institute of Cancer Research in the UK as an irreversible and selective inhibitor of CYP17. It was developed by rational design based on a pregnenolone parent structure after screening of small molecules [Bryce and Ryan, 2012]. It was found that the key molecular feature that provided potent inhibition of CYP17 was the 16,17 double bond and 3-pyridyl substitution [Bryce and Ryan, 2012; Jarman et al. 1998]. Perhaps just as important as its affinity for CYP17 is its lack of antagonism of CYP11B1 and CYP11B2, the enzymes largely responsible for glucocorticoid and mineralocorticoid synthesis respectively. These features made abiraterone, in contrast to ketoconazole, a much more attractive drug given the lack of associated adrenal insufficiency. However, CYP17 does impact the production of glucocorticoids. Upon inhibition of 17α-hydroxylase, cortisol levels fall, and a compensatory rise in adrenocorticotropic hormone (ACTH) levels occurs. This in turn leads to elevated proximal mineralocorticoid levels, although aldosterone itself is suppressed. This secondary rise in ACTH can be blunted with concomitant steroid administration or in theory through the selective inhibition of the CYP17 enzyme C17-20 lyase over 17α-hydroxylase [Vasaitis et al. 2011; Attard et al 2012].

Clinical trials

Abiraterone was studied in two dose-escalation phase I clinical trials. Both were conducted in patients with chemotherapy-naïve CRPC. In the first trial, 21 men were enrolled. Declines in PSA of at least 30%, 50% and 90% were observed in 14 (66%), 12 (57%) and six (29%) patients, respectively. Notable toxicities observed were attributed to mineralocorticoid excess and included hypertension, hypokalemia and lower extremity edema. These were managed with the mineralocorticoid receptor antagonist, eplerenone. Mineralocorticoid excess was felt to be a consequence of elevated ACTH in the context of partially blocking adrenal corticosteroid synthesis. In patients who did not have resolution of mineralocorticoid-associated side effects with eplerenone, dexamethasone was administered to suppress ACTH production [Attard et al. 2008].

The second phase I trial, conducted in 33 patients with CRPC, also included 19 patients previously treated with ketoconazole. In that trial, no dose-limiting toxicities were observed. Mineralocorticoid-associated toxicities were again noted and included hypertension (grade 3, 12%) and hypokalemia (grade 3, 6%; grade 4, 3%). An increase in serum mineralocorticoid levels was observed with abiraterone administration. Eplerenone, β blockers, and diuretics were only modestly effective in mitigating these side effects. It was also noted that corticosteroid administration was associated with a normalization of mineralocorticoid levels and improvements in blood pressure. This trial confirmed a PSA decline of at least 50% in 18 (55%) men, including nine of 19 with prior ketoconazole exposure. Also, out of the 15 patients who developed ketoconazole-refractory disease, seven (46%) responded to abiraterone [Ryan et al. 2010].

Based on these encouraging results, a phase II trial enrolling 58 men with CRPC postdocetaxel chemotherapy was launched. This time, prednisone (5 mg twice daily) was coadministered to negate the ACTH-induced mineralocorticoid side effects observed in the phase I studies. A PSA decline of at least 50% was seen in 22 (36%) men, including 14 of 31 who were ketoconazole naïve and seven of 27 pretreated with ketoconazole. A partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) criteria was seen in four of 22 patients who had evaluable soft-tissue target lesions. Median time to PSA progression was 5.6 months [95% confidence interval 2.7–6.7]. No significant hypertension or hypokalemia were noted, and none of the patients required eplerenone [Danila et al. 2010].

Abiraterone was approved by the US Food and Drug Administration (FDA) and European Medicines Agency based on the results from the pivotal multicenter phase III randomized, placebo-controlled trial COU-AA-301. In this trial, the efficacy of abiraterone was evaluated in men with CRPC who had been previously treated with docetaxel. Abiraterone 1000 mg daily in combination with prednisone 10 mg daily led to a 35.4% reduction in the risk of death compared with placebo plus prednisone, meeting the study’s primary endpoint. The median survival in the abiraterone arm and control arm were 14.8 and 10.9 months respectively (p < 0.0001). In addition, all secondary endpoints were met. Abiraterone in comparison to the control arm led to prolonged time to PSA progression (10.2 versus 6.6 months; p < 0.001); progression-free survival (PFS) (5.6 versus 3.6 months; p < 0.001); and more frequent reductions in the PSA by at least 50% (29% versus 6%; p < 0.0001). Higher rates of mineralocorticoid-related adverse events such as fluid retention, hypertension and hypokalemia were reported in the abiraterone arm, although grade 3 and 4 events were rare [de Bono et al. 2011].

Given the favorable responses seen in early phase trials evaluating abiraterone in chemotherapy-naïve patients, it would stand to reason that its use predocetaxel would lead to favorable outcomes. Abiraterone’s role in this area has yet to be formally defined. However, recently it was announced that COU-AA-302, a phase III trial evaluating abiraterone predocetaxel, was unblinded secondary to a positive interim analysis and an independent monitoring committee’s recommendation. The results of this trial are expected to be released shortly [Janssen Research & Development, LLC, 2012].

Mechanisms of resistance

When patients progress on abiraterone, there is typically a corresponding increase in PSA. Interestingly, there is evidence that prostate cancers with an ERG rearrangement detected prior to receiving hormonal therapy maintain their ERG gene status as well as ERG expression after developing CRPC. These two facts suggest that the androgen–AR pathway continues to be active after a patient’s condition progresses on hormonal therapy. This is likely through ligand-dependent and -independent mechanisms [Knudsen and Scher, 2009; Stein et al. 2012; Attard et al. 2009b].

There is preclinical evidence that abiraterone resistance develops, at least in part, as a result of increased upregulation of intratumoral CYP17 expression. In one model, LuCap prostate xenografts treated with abiraterone showed induction of CYP17 as well as other genes involved in intratumoral androgen synthesis [Cai et al. 2011; Mostaghel et al. 2011]. Treatment with abiraterone can also cause a subsequent increase in upstream steroids, such as deoxycorticosterone, which in theory can act to stimulate a promiscuous AR. In the phase I abiraterone trial, four out of 15 patients whose condition had progressed on single-agent abiraterone were successfully treated with the addition of dexamethasone, presumably through suppression of these upstream steroids [Attard et al. 2008, 2009a]. Constitutively active AR structural variants would be another mechanism for tumor resistance that could result from abiraterone treatment [Hu et al. 2009]. Several additional pathways have also been shown to synergize with the androgen–AR pathway, including the EGFR pathway, Src pathway and phosphoinositide-3 kinase (PI3K) pathway [Cai et al. 2011; Carver et al. 2011; Attard et al. 2009a]. Upregulation or activating mutations along these pathways could in theory reactivate downstream targets of AR signaling.

Biomarkers

While the phase III data clearly show a benefit to using abiraterone postdocetaxel, it was still a minority of men that achieved a PSA reduction of at least 50%. A further minority of patients showed primary resistance to abiraterone. How to determine which patients are most likely to benefit from abiraterone a priori has yet to be defined.

It has been observed that up to 60% of untreated prostate cancers have an associated ETS gene fusion with a hormone-dependent promoter gene, the TMPRSS2–ERG fusion being the most common [Tomlins et al. 2005]. The presence of an ERG rearrangement, as detected through fluorescent in situ hybridization analysis of circulating tumor cells (CTCs), has been shown to associate with the magnitude of maximal PSA decline for patients treated with abiraterone on either the phase I or II clinical trials. For instance, 12 of 15 patients with an ERG rearrangement had a PSA decline of at least 90% whereas only 20 of 62 lacking this rearrangement had such a PSA decline [Attard et al. 2009a, 2009b]. The presence of this fusion gene may prove to be a useful biomarker for predicting a response to abiraterone, but prospective studies are needed to validate these findings. Notably, the predictive utility of ERG fusions in abiraterone-treated patients was not confirmed in a separate study [Danila et al. 2011].

CTC enumeration is another biomarker of interest. Stratification of patients with CRPC based on having a favorable or unfavorable number of CTCs (<5 or ≥5 CTCs/7.5 ml) proved to be an accurate predictor of OS prior to initiating a new cytotoxic therapy. Further, patients who either remained in the favorable group or converted from unfavorable to favorable after starting therapy had a longer OS [de Bono et al. 2008]. Prospective data from the COU-AA-301 trial supported the use of CTC enumeration as a surrogate for OS. CTC conversion from unfavorable to favorable proved to be predictive of OS as early as 4 weeks after starting treatment with abiraterone [Scher et al. 2011].

Recently presented data at the 2012 American Association for Cancer Research (AACR) meeting demonstrated that patients with CRPC and higher serum androgen levels prior to study entry in the COU-AA-301 trial had longer OS. This was true regardless of whether a patient was randomized to placebo or abiraterone [Ryan et al. 2012]. This raises the question of whether androgen levels may be a useful prognostic biomarker regardless of treatment type.

There are clearly other mechanisms by which a patient’s prostate cancer may be androgen driven in the CRPC setting. A better understanding of the biology behind an individual’s CRPC will hopefully lead to a host of biomarkers. The above-mentioned and newer candidate biomarkers will need to be evaluated prospectively to determine their utility in patients for whom abiraterone is being considered.

Open questions

Abiraterone clearly induces a castrate state above that of LHRH agonists/antagonists alone. This in turn has led to the compelling survival benefit seen in the aforementioned trials, and refocused our attention on targeting the androgen–AR pathway in those previously thought to have androgen-independent prostate cancer. However, with this renewed interest in androgen–AR signaling, new questions have arisen.

There is evidence that abiraterone is effective both predocetaxel and postdocetaxel, but the question remains regarding the optimal sequencing of abiraterone with chemotherapy. CYP17 inhibition prior to chemotherapy may prove a more effective strategy given that advanced prostate cancer tends to be more dependent on multiple aberrant pathways [Antonarakis and Eisenberger, 2011]. However, there is the potential that administration of abiraterone predocetaxel may impact one’s response to chemotherapy down the line. It has been shown that taxane-based therapy may be at least in part effective due to taxane-mediated inhibition of nuclear localization of the AR [Zhu et al. 2010]. In patients with CRPC who had either a stable or declining PSA on docetaxel therapy, AR localization has been shown to more often localize to the cytoplasm as opposed to the nucleus compared with those whose condition progresses on docetaxel (70.6% versus 28%, p = 0.02) [Darshan et al. 2011]. This raises the question of potential cross resistance with agents that affect the androgen–AR pathway. Currently it is not known if the timing of abiraterone prechemotherapy or postchemotherapy matters in terms of survival.

The ideal duration of abiraterone therapy is another gray area. Should it be continued indefinitely, akin to our current treatment paradigm used with the LHRH agonist/antagonist, or discontinued upon disease progression? The metabolic implications of prolonged, near total, androgen suppression also need to be determined.

With a host of next-generation drugs that target the androgen–AR pathway on the horizon, the optimal combination of abiraterone with these agents needs to be worked out. Our understanding of the biology behind prostate cancer and regulation of the AR presents an opportunity to design a host of rational clinical trials. However, this will require cooperation between investigators and the numerous companies involved in the development of these drugs.

Orteronel (TAK-700)

Given the drawbacks to long-term corticosteroid use, there has been interest in developing new CYP17 inhibitors that do not require steroid coadministration, especially if these agents are to be used in men with earlier disease states. Drugs that more specifically inhibit C17-20 lyase as opposed to 17α-hydroxylase may be less likely to require concomitant prednisone (Figure 2). Orteronel (TAK-700) is a next-generation CYP17 inhibitor with a higher specificity for C17-20 lyase inhibition. The preliminary phase I/II data for orteronel were recently presented at the American Society of Clinical Oncology Genitourinary (ASCO GU) 2012 symposium. Orteronel showed PSA response rates (≥50% decrease) at 12 weeks of 63%, 50%, 41% and 60% in the 300 mg twice daily, 400 and 600 mg twice daily plus prednisone and 600 mg daily groups respectively. A total of 97 patients were enrolled and 51 had RECIST evaluable disease. Of those, 10 had a partial response, 22 had stable disease and 15 had disease progression. Overall the mean circulating tumor cells (CTCs) decreased from 16.6 (per 7.5 ml blood) to 3.9 at 12 weeks. Despite some groups not receiving concomitant prednisone, side effects associated with mineralocorticoid excess were uncommon (8% with grade ≥3 hypokalemia). Based on these initial results, orteronel is currently being investigated in two placebo-controlled randomized phase III trials [Agus et al. 2011]. The first study is evaluating patients with docetaxel-refractory metastatic CRPC, while the second study is targeting a similar population of men who have not received prior chemotherapy. Notably, these studies failed to take advantage of the theoretical selective C17-20 lyase activity of orteronel, as neither trial is evaluating a steroid-free treatment regimen in these patients.

Galeterone (TOK-001)

Another next-generation CYP17 inhibitor, galeterone (TOK-001), has the added advantage of disrupting multiple androgen signaling pathways simultaneously, resulting in downregulation of the AR and competitively inhibiting androgen binding and AR translocation into the nucleus [Vasaitis et al. 2008, 2011; Handratta et al. 2005]. This drug is currently being evaluated in the context of a phase I/II trial (ARMOR1). Preliminary results were recently released at the 2012 AACR annual meeting. In general, the drug was well tolerated with the most common adverse events being fatigue (36.7%), aspartate aminotransferase (32.7%) and alanine aminotransferase elevations (30.6%), nausea (28.6%) and diarrhea (26.5%). Serious adverse events were rare. Twenty-four (49%) patients had a PSA reduction of at least 30% and 11 (22%) had a PSA reduction of at least 50% [Taplin et al. 2012].

Enzalutamide (MDV3100)

The primary mode of treatment for metastatic prostate cancer has historically focused on targeting androgen–AR signaling by decreasing the amount of ligand (androgens) available for binding to the AR. Enzalutamide (MDV3100) is a newer agent that targets this pathway through binding of the AR itself and preventing nuclear translocation and coactivator recruitment of the ligand–receptor complex. In contrast with other AR antagonists, such as bicalutamide, that exhibit some degree of AR agonism, enzalutamide is a pure antagonist with no agonistic activity. It has also been shown to lead to apoptosis in LNCaP/AR xenograft tumors growing in castrated mice, whereas bicalutamide only leads to slowed tumor growth [Tran et al. 2009]. A phase I/II trial that enroled 140 patients (in the predocetaxel and postdocetaxel settings) led to decreases in PSA of at least 50% in 56% of patients, soft tissue responses in 22% with measurable disease, and stabilization of bone disease for at least 12 weeks in 56% [Scher et al. 2010].

These promising results have led to the initiation of two phase III trials: the first evaluating enzalutamide in the postdocetaxel window (AFFIRM) and the second in the predocetaxel window (PREVAIL). Mature results from the AFFIRM trial were recently presented at ASCO GU this year. A total of 1199 patients were enrolled. At the time of a planned interim analysis, an OS benefit was observed in the enzalutamide arm compared with the placebo arm (18.4 versus 13.6 months; p < 0.0001) with a hazard ratio for death of 0.631. Based on these results, the Independent Data Monitoring Committee recommended that the study be unblinded and the study drug be offered to all patients who had initially been randomized to placebo [Scher et al. 2012a]. In addition, compared with placebo, enzalutamide improved PSA response rates (PSA decline ≥50%) (1.5% versus 54%), objective response rates in those with measurable disease (3.8% versus 28.9%), and PFS (2.9 versus 8.3 months). Fatigue was the most common side effect of enzalutamide, while seizure activity was reported in 0.6% of enzalutamide-treated patients (versus 0% of placebo-treated patients). Serious adverse events were equivalent in the two treatment arms (33.5% versus 38.6% in placebo-treated patients) [Scher et al. 2012b]. Based on these results, FDA approval for enzalutamide in the postchemotherapy setting is expected later this year. As supplemental evidence of enzalutamide’s activity across a wider disease spectrum, the PREVAIL trial is currently recruiting patients who have not received prior docetaxel chemotherapy, and is expected to complete in 2014. Importantly, one potential advantage of enzalutamide over the CYP17 inhibitors is its lack of requirement for corticosteroids. Therefore, this agent would be expected to be used more easily in the minimal-disease setting (e.g. in men with nonmetastatic CRPC, or biochemically recurrent noncastrate prostate cancer). Such trials are currently in progress or in development.

ARN-509

ARN-509 was developed in an attempt to build on the success of enzalutamide. Like enzalutamide, this drug works through competitive AR inhibition that is purely antagonistic. It has also been shown to reduce efficiency of nuclear translocation of the AR and impairs AR binding to androgen-response elements of DNA. In a clinically validated mouse xenograft model, ARN-509 possibly appeared more efficacious than enzalutamide. A maximal therapeutic effect was achieved at 30 mg/kg/day with ARN-509 as opposed to 100 mg/kg/day for enzalutamide [Clegg et al. 2012]. In addition, ARN-509 was comparably less effective at penetrating the blood–brain barrier in this mouse model, suggesting that it may have fewer off-target inhibitory effects on γ-aminobutyric acid type A, which is one presumed mechanism of seizure activity with enzalutamide [Foster et al. 2011].

This preclinical evidence for ARN-509 as a promising therapeutic agent has led to the opening of a phase I/II trial evaluating the drug in patients with various CRPC states: those with nonmetastatic CRPC, as well as those with metastatic chemotherapy-naïve CRPC (both pre- and post-abiraterone cohorts). Phase I results were reported at the 2012 ASCO GU symposium. Rathkopf and colleagues found that ARN-509 was active across all doses tested in the phase I dose escalation component of the trial. A total of 24 patients were included in the study with 12 (55%) having a PSA decline of at least 50%. Most toxicities were grade 1–2 and included fatigue (38%), nausea (29%), and pain (24%). Only one patient had a grade 3 adverse event (abdominal pain). Based on these results a recommended phase II dose of 240 mg was selected for study in the phase II portion of the trial [Rathkopf et al. 2012]. This component completed enrolment in June 2012.

Conclusion

CRPC remains an invariably fatal disease. Fortunately, the number of therapies that are effective in this window have been on the rise over the past couple of years. CYP17 inhibition clearly provides a new tool in targeting the androgen–AR signaling pathway. However, when this pathway is activated at the postreceptor ligand binding level or through nonhormonally mediated mechanisms, drugs such as abiraterone may not suffice. Furthermore, even in patients who initially respond to abiraterone, resistance always develops in months to several years.

Given that many pathways have been implicated in the growth of CRPC, it is likely that a combination of the aforementioned drugs would lead to better outcomes than any single agent. A search of trial registries reveals several ongoing clinical trials evaluating abiraterone’s use in conjunction with other targeted antineoplastic agents (Table 1). These include trials to evaluate its use with the PI3K inhibitors GDC-0068 and GDC0980, the 5-α-reductase inhibitor dutasteride, the antiangiogenesis drug AMG 386, the dual c-Met and VEGFR2 inhibitor cabozantinib, as well as with the Src inhibitor dasatinib and the multitargeted tyrosine kinase inhibitor sunitinib. Abiraterone is also being evaluated for use along with the standard cytotoxic chemotherapeutics, cabazitaxel and docetaxel. Drugs that work at different nodes along the androgen–AR signaling pathway, such as enzalutamide or ARN-509, are not currently being investigated clinically in conjunction with CYP17 inhibitors, although such trials are in development.

Table 1.

Select ongoing clinical trials evaluating abiraterone in combination with other targeted and cytotoxic agents in the treatment of prostate cancer.

Investigational agent combined with abiraterone	Investigational agent mechanism	Trial phase (NCT identifier)	Disease description	Trial description
Sipuleucel-T	Autologous APC-based immunotherapeutic	Phase II (NCT01487863)	CRPC	Combined versus sequential treatment
Cabazitaxel	Cytotoxic chemotherapy	Phase I/II (NCT01511536)	CRPC	Combined treatment
Docetaxel	Cytotoxic chemotherapy	Phase Ib (NCT01400555)	CRPC	Combined treatment
Veliparib	PARP inhibitor	Phase II (NCT01576172)	CRPC	Combined versus monotherapy with abiraterone
GDC-0068 GDC-0980	PI3K inhibitors	Phase Ib/II (NCT 01485861)	CRPC postdocetaxel therapy	Combined versus monotherapy with abiraterone
Dutasteride	5-α-reductase inhibitor	Phase II (NCT01393730)	CRPC	Combined treatment
AMG 386	Antiangiogenesis	Phase II (NCT01553188)	CRPC	Combined treatment
Cabozantinib	c-Met and VEGFR2 inhibitor	Phase I (NCT01574937)	CRPC postchemotherapy	Combined treatment
Sunitinib Dasatinib	Multitargeted TKIs	Phase II (NCT01254864)	CRPC predocetaxel or postdocetaxel chemotherapy	Combined versus monotherapy with abiraterone

APC, antigen-presenting cell; CRPC, castrate-resistant prostate cancer; NCT, national clinical trial; PARP, poly ADP ribose polymerase; PI3K, phosphoinositide-3 kinase; VEGFR2, vascular endothelial growth factor receptor 2.

Another area in need of further investigation is biomarker development. Given the vast number of new agents expected to gain FDA approval for advanced prostate cancer in the next few years, the ability to predict which agent, or combination of agents, a patient will respond to is paramount. In the case of abiraterone, there is evidence that a TMPRSS2-ERG fusion gene may predict a particularly robust response to CYP17 inhibition, although the predictive utility of ERG fusions has not been confirmed by all investigators. Baseline CTCs and CTC conversion are other potential predictive biomarkers and have been shown to correlate well with OS, making them a good surrogate endpoint for future trials. As we develop an ever-greater ability to modulate the androgen–AR pathway at different points along its signaling cascade, predictive biomarker discovery and validation will be critical. Oncology has long promised an era of personalized medicine, and with an ever-expanding war chest of tools to fight prostate cancer, this is rapidly becoming a reality. A new era of prostate cancer therapeutics is born.

Footnotes

Funding

This work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

None of the authors declare any financial or other potential conflicts of interest related to this work.

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