Chemotherapeutic inhibitors in the treatment of prostate cancer.

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Chemotherapeutic inhibitors in the treatment of prostate cancer a

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Rahul R Deshmukh , Sara M Schmitt , Clara Hwang & Qing Ping Dou

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a

Wayne state University, Karmanos Cancer Institute, School of Medicine, Department of Pathology, 540.1 HWCRC, 4100 John R Road, Detroit, MI 48201, USA b

Wayne State University, Karmanos Cancer Institute, School of Medicine, Department of Oncology, Detroit, MI 48201-2013, USA c

Wayne State University, Karmanos Cancer Institute, School of Medicine, Department of Pharmacology, Detroit, MI 48201-2013, USA+1 313 576 8301; +1 313 576 8307; d

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Wayne State University, Karmanos Cancer Institute, School of Medicine, Detroit, MI 48201-2013, USA e

Henry Ford Hospital, Josephine Ford Cancer Center, Division of Hematology/Oncology, Department of Internal Medicine, Detroit, MI 48202, USA Published online: 25 Oct 2013.

To cite this article: Rahul R Deshmukh, Sara M Schmitt, Clara Hwang & Qing Ping Dou (2014) Chemotherapeutic inhibitors in the treatment of prostate cancer, Expert Opinion on Pharmacotherapy, 15:1, 11-22 To link to this article: http://dx.doi.org/10.1517/14656566.2014.852184

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Review

Chemotherapeutic inhibitors in the treatment of prostate cancer

Downloaded by [University of California, San Diego] at 04:38 02 September 2015

Rahul R Deshmukh, Sara M Schmitt, Clara Hwang & Qing Ping Dou† †

1.

Introduction

2.

Key players in prostate cancer

3.

Current treatment options

4.

Conclusion

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Expert opinion

Wayne State University, Karmanos Cancer Institute, School of Medicine, Departments of Oncology and Pathology, Detroit, MI, USA

Introduction: Prostate cancer being the second leading cause of death in men in Western countries remains a major challenge in healthcare. Several novel agents targeting signaling pathways in prostate cancer have recently been approved by the US Food and Drug Administration (FDA) but there is still an unmet need for new treatment strategies for castration-resistant prostate cancer (CRPC). Areas covered: This review provides a broad overview of prostate cancer therapeutics and highlights key players in the biology of prostate cancer as well as first- and second-line treatments for CRPC. Keywords ‘chemotherapeutic agents’, ‘prostate cancer’, ‘Phase III clinical trials’ and ‘US FDA approval’ were used for search in PubMed and clinicalTrials.gov databases and the obtained literature was reviewed and summarized. Expert opinion: Owing to the advances in screening and diagnostic techniques, the majority of prostate cancer cases are diagnosed at an early stage resulting in an almost 100% 5-year survival rate. Recently FDA-approved novel agents (e.g., abiraterone acetate and enzalutamide) have provided new hope in the fight against prostate cancer. However, CRPC remains an incurable disease. Identification of mechanisms of resistance, new biomarkers, appropriate clinical trial end points and novel treatments holds the key for the future of prostate cancer therapy. Keywords: abiraterone, androgen deprivation therapy, androgen receptor signaling, bicalutamide, cabazitaxel, castration-resistant prostate cancer, docetaxel, enzalutamide, estramustine, flutamide, ketoconazole, megestrol, mitoxantrone Expert Opin. Pharmacother. (2014) 15(1):11-22

1.

Introduction

Prostate cancer is one of the most common malignancies and the second leading cause of cancer-related mortality in men in the United States [1]. Circulating androgens are the primary drivers of prostate cancer growth; hence, following metastasis, patients are initially treated with androgen deprivation therapy (ADT) by surgical or pharmacological castration [2]. The standard first-line treatment for metastatic prostate cancer involves ADT with bilateral orchiectomy, luteinizing hormone-releasing hormone (LHRH) agonist with or without anti-androgen or LHRH antagonist. Additional treatment with anti-androgens, for those who did not receive them as first-line therapy, or androgen withdrawal, is given as second-line therapy [3]. Unfortunately, after an initial benefit from ADT, the disease progresses despite castrate levels of testosterone (< 50 ng/dl) [4]. This disease stage is called castration-resistant prostate cancer (CRPC), formerly known as hormone-refractory prostate cancer. Prostate-specific antigen (PSA) is a glycoprotein exclusively secreted by normal and neoplastic prostate cells. The rate of change in the serum PSA levels is used as a predictive marker in prostate cancer outcome [5]. During CRPC, progressive disease is identified with increases in serum PSA, radiographic progression or worsening of symptoms [6]. Prostate cancer may eventually metastasize to other organs, 10.1517/14656566.2014.852184 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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R. R. Deshmukh et al.

Article highlights. . . .

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Circulating androgens are the primary drivers of prostate cancer growth. The disease progresses despite castrate levels of testosterone. The recent advances in the understanding of the molecular biology of this disease have led to the discovery of more specific, advanced agents for its treatment. Understanding the mechanisms of primary and secondary resistance remains a great challenge for future prostate cancer drug design and discovery efforts. Identification of new biomarkers as well as more relevant clinical trial end points may hold the key for the future of prostate cancer therapy.

This box summarizes key points contained in the article.

especially to bones. Metastatic CRPC (mCRPC) leads to morbidity and poor quality of life [4]. Owing to the introduction of ADT and chemotherapy for metastatic disease, overall survival (OS) may increase up to 5 years from the first metastases [3]. 2.

Key players in prostate cancer

3.

Although androgen receptor (AR) signaling is thought to be the key player driving prostate cancer growth, the exact molecular mechanism for CRPC has not been clearly understood. Multiple mechanisms have been proposed for the progression of CRPC including, but not limited to: i) AR overexpression, ii) multiple point mutations in AR leading to enhanced sensitivity to androgen or activation by other steroids or even anti-androgens, iii) expression of steroidogenic enzymes in prostate cancer cells leading to increased intracellular production of steroids, iv) AR activation due to crosstalk between different signaling pathways, v) development of androgen-independent isoforms of AR, and vi) altered expression of coactivators and/or corepressors of AR [2,7-10]. It should be noted that the ADT should be continued in CRPC to suppress growth of remaining hormone-sensitive cells [3]. Microenvironment around the prostate cancer cells also plays an important role in disease progression. During the progression of prostate cancer, the stroma surrounding prostate cells shows abnormal cellular composition, histology and altered intercellular communication. The stromal cells also secrete enzymes and soluble factors that are responsible for crosstalk with tumor cells leading to disease progression. As bone microenvironment promotes tumor cell growth and stimulates angiogenesis, metastasis to the bones is commonly observed in CRPC patients [2]. Clinical and experimental data also suggest that cytochrome P450C17 (CYP17) has an important role in prostate cancer progression. It catalyzes crucial steps for the biosynthesis of 12

testosterone and estradiol (e.g., 17a-hydroxylation of C21 steroids and cleavage of the C17,20 bond of C21 steroids) and has been validated as a therapeutic target for prostate cancer treatment [3]. The insight into the molecular biology of CRPC has led to the development of advanced, targeted therapeutic agents for CRPC, including the autologous immunotherapy sipuleucel-T, CYP17 inhibitor abiraterone acetate (AA), radiotherapeutic agents such as radium-223 and cabazitaxel as the second-line chemotherapy following progression after docetaxel treatment, and the bone-targeting agent denosumab. The US Food and Drug Administration (FDA) approved the dendritic cell-based vaccine, sipuleucel-T, for the treatment of asymptomatic or minimally symptomatic CRPC. A calcium mimetic and a-emitter radiopharmaceutical radium-223 was also recently approved for the treatment of CRPC [11]. As chemotherapeutic agents in CRPC are the main focus of this article, we have not discussed either immunotherapies or radiotherapies for the treatment of CRPC. This article is aimed at reviewing and discussing different chemotherapeutic treatment options (Table 1) which should be considered after the failure of primary and secondary hormonal therapies in prostate cancer [3].

Current treatment options

Androgen deprivation therapy Because of the importance of androgens and the AR in the prostate, one treatment option for prostate cancer is ADT. ADT is classified as any treatment that causes AR to be inactivated, and it can be done via decreasing testosterone production or AR blockade, achieved by either surgical or medical castration, anti-androgens or any combination of these (Figure 1) [12]. The aim of both surgical and medical castration is to lower the levels of serum testosterone to a point at which stimulation of prostate cancer cells is minimal. Bilateral orchiectomy as a means of surgical castration has been effectively used as a strategy to decrease testosterone levels since the early 1940s when a paper detailed the medical improvement in advanced prostate cancer patients treated with estrogens and surgical castration [13]. A preference for organ preservation has led to the more common form of medical castration by ADT using gonadotropin-releasing hormone (GnRH) agonists and antagonists. GnRH agonists, such as leuprolide and goserelin, bind to GnRH receptors in the pituitary gland, causing an initial release of luteinizing and follicle-stimulating hormones (LH and FSH, respectively) and a subsequent increase in serum testosterone. It is important to be aware of the possibility of worsening disease-related symptoms during this time, which can be mitigated by additional therapy such as antiandrogens or testosterone synthesis inhibitors. After 4 -- 6 weeks, GnRH receptors are downregulated, decreasing pituitary production of LH and FSH and finally leading to reduced serum testosterone. 3.1

Expert Opin. Pharmacother. (2014) 15(1)


Table 1. Selected therapeutic agents in the treatment of prostate cancer. Drug

Mechanism of action

Docetaxel

Cabazitaxel

Bicalutamide


AA

Enzalutamide (MDV3100)

Common/major side effects

Binds to free tubulin leading to formation of stable microtubule and inhibiting its disassembly resulting in inhibition of mitosis and impairs nuclear translocation and activity of AR Binds to tubulin and inhibits disassembly of microtubules, causing mitotic arrest at the metaphase--anaphase transition, leading to cell death AR antagonist, accelerates AR degradation Irreversibly inhibits 17a-hydroxylase CYP17A1, which is expressed in testicular, adrenal, and prostatic tumor tissues and required for androgen biosynthesis AR antagonist, competitively binds to AR and prevents its nuclear translocation and coactivator recruitment in the ligand--receptor complex

Neutropenia, leukopenia, febrile neutropenia and thrombocytopenia [41,76]

Neutropenia, leukopenia, anemia, neurotoxicity, diarrhea, fatigue, asthenia and back pain [66,68] Gynecomastia, hot flashes, elevated levels of transaminase, jaundice, asthenia and pruritus [77-79] Urinary tract infection, fluid retention, peripheral edema, hypertension, hypokalemia and fatigue [60] Fatigue, diarrhea, musculoskeletal pain, headache, hypertension and hot flashes [61,72]

Cholesterol Pregnenolone 17 α-hydroxylase of CYP17 Hypothalamus

Abiraterone + Prednisone

17-OH pregnenolone C17,20-lyase of CYP17 Dehydroepiandrosterone

Gonadotropin releasing hormone Leuprolide Goserelin Degarelix

Androstenedione Testosterone

Leutinizing and follicle stimulating hormone

Surgical castration

Androgen production

Androgen receptor binding and signaling Docetaxel + Prednisone

Prostate cancer growth and progression

Bicalutamide, Flutamide Nilutamide, Enzalutamide

Mitoxantrone + Prednisone

Cabazitaxel + Prednisone

Figure 1. Treatment options in prostate cancer are shown: androgen signaling plays major role in prostate cancer growth and progression. The different treatment options for prostate cancer include ADT via bilateral orchiectomy, LHRH agonist with or without anti-androgen or LHRH antagonist. The standard first-line chemotherapy includes docetaxel-based regimens. The additional treatment with anti-androgens or androgen withdrawal is given to the patients as a second-line therapy.

Additionally, GnRH antagonists, which lack the ability to stimulate androgens on initial treatment [14,15], have also been in development for some time. GnRH antagonists have proven difficult to synthesize due to low potency and solubility problems, in addition to difficulty in designing

sustained duration formulations that included sufficient antagonist levels. Abarelix was the first GnRH antagonist that was successfully synthesized in a sustained duration formulation to reach clinical trials [15]. Abarelix blocks GnRH and inhibits LH production, resulting in suppression of


13



testosterone and dihydrotestosterone (DHT), and the lack of initial androgen surge prevents temporary worsening of the cancer. Owing to adverse effects such as anaphylactic reactions, abarelix was withdrawn from the US market in 2005 [16]. In addition, another GnRH antagonist, degarelix, has been shown in Phase III trials to be at least as effective as leuprolide with a much faster reduction in testosterone [17]. GnRH agonists and antagonists, similar to surgical castration, are unable to inhibit testosterone production from nongonadal sources such as the adrenal gland. The current consensus is that there is very little difference, clinically, between surgical and medical castrations [18]. However, despite the initial benefits of medical or surgical castration, many patients progress to CRPC, which leads to the addition of nonsteroidal anti-androgens to GnRH agonists for maximum androgen blockade [19]. Anti-androgen agents bind directly to AR, competitively inhibiting the binding of testosterone and DHT. When given as monotherapy, testosterone levels remain high, or even increase, such that side effects are more tolerable than with castration. Non-steroidal anti-androgens such as bicalutamide, flutamide and nilutamide may also be used as alternatives to medical or surgical castration in advanced prostate cancer, but they are not the preferred treatments when given as monotherapy. While no study has directly compared these agents in patients, bicalutamide does appear to be superior to either flutamide or nilutamide as it binds AR with the highest affinity, has the longest half-life and has a relatively better toxicity profile compared with the other two agents [20]. Importantly, these antagonists may also have AR agonist activity, especially under circumstances associated with CRPC, so their use in these cases may be limited [10,21-23], but in general, the combination of castration and anti-androgen treatment does seem to afford patients a small survival advantage compared to either treatment alone [24]. While its use does have benefits in many patients, many side effects of ADT have been reported. These include: vasomotor flushing, fatigue, anemia, sarcopenia, increased risk for cardiac events, decreased sexual desire, sexual dysfunction, gynecomastia, metabolic syndrome, insulin resistance, neuropsychological symptoms, osteoporosis and bone fractures. The combination of these and the potential for adverse effects on prostate cancer outcome and quality of life have limited the use of ADT as primary therapy [25]. An analysis of more than 19,000 men with localized prostate cancer in the Surveillance Epidemiology and End Results database revealed that the use of ADT as primary treatment was associated with an increased risk of prostate cancer-specific mortality, with no difference in overall mortality [26]. Additionally, a randomized Phase III trial (EORTC 30846) of men receiving early versus deferred ADT who did not undergo radical prostatectomy reported no benefit from the early approach, and at the median follow up of 9.6 years, 62.9% of patients had died (76% of prostate cancer), with a 23% non-significant trend in favor of early treatment [27]. 14

Second-line hormone therapy Early clinical investigation led to the observation that treatment with estrogens could improve disease symptoms in men with prostate cancer. In the 1960s, a series of large trials in men with locally advanced or metastatic prostate cancer was performed by the Veterans Administration Cooperative Urologic Research Group. Patients were randomized to receive placebo, high dose diethylstilbestrol (DES), orchiectomy or orchiectomy with DES. However, the 5-year OS was not significantly improved with ADT, in part because men who received DES had an increased risk of death from cardiovascular or cerebrovascular incidents [28-32]. Other studies showed that GnRH agonists were similarly effective when compared to DES, but resulted in much less cardiac toxicity, relegating DES to be used only as second-line hormonal therapy [33]. The anti-inflammatory properties of corticosteroids have led to their use in the treatment of human cancers, including prostate cancer, in which they may have a direct effect on pain associated with bone metastasis [34,35]. Corticosteroids mimic endogenous cortisol and mineralocorticoids, activating the glucocorticoid receptor to upregulate anti-inflammatory and downregulate proinflammatory proteins [36]. Because of side effects associated with other treatment strategies and the fact that corticosteroids are anti-inflammatory, their use has become common in the treatment of prostate cancer. Premedication with dexamethasone and co-treatment with prednisone are common in patients treated with docetaxel, primarily to reduce side effects, as studies comparing patients treated with docetaxel with or without prednisone showed no difference in reduction of PSA levels between the groups; thus, the use of corticosteroids has very little positive or negative effect on the efficacy of docetaxel [37-41]. Corticosteroids are also used concomitantly with second-line hormone therapies such as ketoconazole and abiraterone, which act by disrupting androgen biosynthesis in a dose- and timedependent manner. This results in decreased cortisol and mineralocorticoid levels, which could lead to adrenal insufficiency or crisis that can be prevented by corticosteroid treatment [42]. Finally, corticosteroid treatment may also negatively regulate adrenocorticotropic hormone (ACTH) release and thus adrenal androgen synthesis. In support of this hypothesis, men treated with prednisone have reduced systemic levels of adrenal androgens which correspond with clinical benefits such as pain relief [35]. Ketoconazole is an imidazole antifungal agent with weak nonspecific CYP17 inhibitory properties, but very high doses are required for these activities, and thus treatment is associated with neurological, respiratory and hepatic toxicities [43]. One Phase III trial compared anti-androgen withdrawal alone to anti-androgen withdrawal plus ketoconazole, and PSA declines of at least 50% occurred in 11 versus 27% of patients and objective tumor responses were observed in 2 versus 20% of men with measureable disease, respectively. However, 3.2




median survival did not differ [44]. A more recent study evaluated the efficacy of ketoconazole alone following progression to a castration-resistant state. Patients were randomized to receive either 200 or 400 mg ketoconazole three times daily, with measurement of time to PSA progression, duration of response and frequency of side effects. Of patients receiving 200 mg ketoconazole, 37.8% demonstrated a PSA response, compared with 57.1% of patients receiving 400 mg. Time to progression following a > 50% PSA response was 7.5 versus 11.5 months and median duration of response was 5.5 and 9 months in the 200 and 400 mg groups, respectively. Thus, ketoconazole alone is able to cause a PSA response in castration-resistant patients with a comparable toxicity profile to previous studies [45]. Chemotherapeutic agents Although secondary hormonal therapies such as estrogen and ketoconazole may benefit patients with prostate cancer, no OS benefit has been demonstrated for these agents. Traditional chemotherapeutic agents are still considered the firstline treatment for advanced prostate cancer patients who progress on hormonal therapy, with docetaxel currently favored as the first-line chemotherapeutic agent. In addition to docetaxel, mitoxantrone and estramustine have also been used in the treatment of advanced prostate cancer. Mitoxantrone is an anthracenedione agent that exerts its antitumor activity by inhibition of topoisomerase II, which results in disruption of DNA synthesis and repair, as well as DNA intercalation [46]. Estramustine is a nitrogen mustard estradiol-17b-phosphate derivative with the ability to disrupt microtubule dynamics and decrease plasma testosterone. Following gastrointestinal (GI) absorption, estramustine is metabolized into estrone and estradiol, which penetrate prostate cells to cause microtubule depolymerization and inhibit mitosis [47]. Neither mitoxantrone (in combination with prednisone) nor estramustine are currently used as first-line therapies for CRPC, due to the superiority of docetaxel and other agents. Docetaxel exerts its antitumor effects by: i) disrupting the cellular microtubule network that is required for mitotic and interphase cellular functions, ii) binding free tubulin and promoting its assembly into microtubules and iii) inhibiting microtubule disassembly, all with the final result of production of abnormally functioning microtubule bundles which ultimately inhibits mitosis. In the context of prostate cancer, docetaxel has also been shown to impair nuclear translocation and activity of AR, which suppresses tumor growth [48]. The pharmacokinetic profile of docetaxel is consistent with a three-compartment model based on a study in which patients were given 20 -- 115 mg/m2 docetaxel. Half-lives for a, b and g phases were 4 min, 36 min and 11.1 h, respectively, and mean total body clearance was 21 l/h/m2 with a mean steady-state volume of distribution of 113 l, with > 95% docetaxel bound to plasma proteins. Importantly, pretreatment with dexamethasone or co-treatment with prednisone did 3.3

not alter the drug’s clearance but clearance did drastically increase following castration compared to before, likely as a result of increased hepatocellular uptake [49]. In contrast, docetaxel is metabolized by CYP3A4 and thus, its metabolism may be affected by coadministration of agents that regulate or are metabolized by CYP3A4. Additionally, a mean reduction in clearance of 27% was observed in patients with hepatic impairment. Several Phase II and retrospective studies have reported the clinical benefit of docetaxel treatment. A noncomparative, multicenter, prospective Phase II study of 43 patients with Gleason scores of 5 -- 10 receiving 3-weekly docetaxel 70 mg/m2 plus 5 mg twice daily prednisone administered for a maximum of 10 cycles showed an overall tumor response rate of 44.2% with 19 patients achieving partial response. The median duration of response was 19.3 weeks and PSA response (decline of ‡ 50% for at least 3 weeks) was reported in 44.4% of patients [50], thus suggesting that docetaxel is effective in this subset of patients. Additionally, a study of weekly docetaxel in patients who had progressed on mitoxantrone reported on the safety and activity of docetaxel. Of the 20 patients, 9 patients had at least a 50% reduction in PSA level, with a median time-to-progression of 5 months and median survival was 13 months [51]. Another study showed that a 3-weekly schedule is successful after mitoxantrone with at least 50% PSA reduction in 85% of patients with a 60% pain response [52]. Finally, Phase III clinical trials have compared the use of docetaxel to the previously favored treatment option, mitoxantrone, and have led to the current use of 3-weekly docetaxel--prednisone as the first-line therapy for advanced prostate cancer. In both the TAX 327 and Southwest Oncology Group (SWOG) trials, patients assessed their pain levels daily using the Present Pain Intensity scale of the McGill Pain Questionnaire-Short Form. The TAX 327 study was a randomized non-blind study comparing survival in men with progressive CRPC who were treated with mitoxantrone or docetaxel in combination with prednisone. The primary end point of the study was OS with secondary end points of pain and PSA responses and quality of life [53]. Patients were randomized to receive weekly docetaxel (30 mg/m2) for 5 out of 6 weeks, 3-weekly docetaxel (75 mg/m2) or the standard 3-weekly mitoxantrone regimen (12 mg/m2); all patients received twice daily prednisone (5 mg) and docetaxel treatment was preceded by dexamethasone. The study reported a significant increase in survival time with 3-weekly docetaxel (median survival = 18.9 months) compared to mitoxantrone (median survival = 16.5 months), but not with weekly docetaxel (median survival = 17.4 months). Pain reduction was also the most significant in the 3-weekly docetaxel group: 35% compared with 31 and 22% on weekly docetaxel and mitoxantrone, respectively. Patients in the docetaxel groups reported more side effects, with treatment discontinuation in 11 and 16% of patients in the 3-weekly and weekly docetaxel groups and 10% in the mitoxantrone group. Common side effects


15



resulting in discontinuation included fatigue, musculoskeletal or nails changes, sensory neuropathy and infection in the docetaxel group and cardiac dysfunction in the mitoxantrone group. In addition, though it did not result in discontinuation, grade 3 -- 4 neutropenia was observed in 32% of the 3-weekly docetaxel group, in 22% of the mitoxantrone group and in 1.5% in the weekly docetaxel group [53]. The SWOG 9916 study compared docetaxel plus estramustine to mitoxantrone plus prednisone in CRPC patients, 18% of whom had rising PSA levels as their only manifestation of progression [54,55]. The docetaxel plus estramustine group received 3-weekly 60 mg/m2 docetaxel with 280 mg estramustine (thrice daily for 5 days) and premedication with dexamethasone. The mitoxantrone plus prednisone group received 3-weekly 12 mg/m2 mitoxantrone with continuous twice daily prednisone. The docetaxel plus estramustine group had markedly improved overall and disease-free survival (median survival = 17.5 months), compared with the mitoxantrone plus prednisone group (median survival = 15.6 months). The PSA response was also higher in the docetaxel group, but pain relief was similar in both groups. Similar to the TAX 327 study, toxicity was also greater in the docetaxel plus estramustine group compared to mitoxantrone plus prednisone, with 16 and 10% of patients discontinuing treatment, respectively. GI, neurological, cardiac and metabolic events were significantly more common in the docetaxel plus estramustine group; aspirin and warfarin were added halfway through the study in an attempt to counteract these effects but did not appear to reduce the risk of severe complications. Finally, while incidence of grade 3 -- 4 neutropenia did not differ between groups, febrile neutropenia was reportedly higher in the docetaxel plus estramustine arm (5 vs 2%) [54,55]. The survival advantage afforded by docetaxel treatment over mitoxantrone has, thus, led to its use as the first-line therapy for advanced prostate cancer. 3.4

New agents Abiraterone acetate

3.4.1

17-a-hydroxylase/C17,20-lyase (CYP17) is a microsomal enzyme involved in the androgen production in testes, adrenal glands and tumor tissues. It catalyzes biosynthesis of testosterone precursors namely dehydroepiandrosterone and androstenedione. Therefore, CYP17 inhibition leads to significant decrease in the synthesis of cortisol, androgens and estrogens [56]. These observations led to the discovery of androgen biosynthesis inhibitors such as abiraterone for the treatment of CRPC (Figure 1) [57,58]. Based on the preclinical data from various studies, a Phase I dose--escalation study of abiraterone was conducted on 21 patients with chemotherapy-naı¨ve CRPC. These patients were evaluated for disease response and toxicities. AR becomes highly promiscuous in CRPC, so the accumulation of precursor steroids upstream of CYP17 might still carry out androgen signaling due to their weak agonist activity. As the supplemental glucocorticoid mitigates glucocorticoid deficiency 16

which is expected with CYP17 inhibition as well as subsequent mineralocorticoid excess, the investigators added low-dose dexamethasone to the AA regime. At doses > 750 mg/day of AA, plateau in the endocrine effect was observed and 1000 mg/day was selected as optimal dose for next studies. Of the 21 (57%) patients, 12 patients exhibited PSA decline of ‡ 50% from the baseline. When the disease progressed, addition of daily dexamethasone to AA resensitized the tumor to AA as shown by the decline in PSA ranging from 36 to 99% in 4 of 15 patients (27%). In a double-blind, Phase III clinical trial (NCT00887198), 1088 mCRPC patients who had not been exposed to chemotherapy were randomly divided into two groups, abiraterone (1000 mg) plus prednisone (5 mg twice daily) and placebo plus prednisone. The results show that abiraterone improved radiographic progression-free as well OS with delay in clinical decline and initiation of chemotherapy [59]. In another double-blind, Phase III clinical trial (NCT00638690), abiraterone prolonged OS in mCRPC patients who received prior chemotherapy [60]. Adverse effects such as hypertension, hypokalemia and fluid retention were commonly observed in patients indicating mineralocorticoid excess [60]. Based on these encouraging results, the US FDA approved 1000 mg/day of abiraterone orally in combination with 5 mg prednisone orally twice a day for the treatment of mCRPC patients [61]. AA is an orally active agent which is converted in vivo to abiraterone, a specific and irreversible inhibitor of CYP17, thus causing significant decrease in testosterone levels below the detection limit of 1 ng/dl. Inhibition of cortisol synthesis leads to an increase in ACTH production and thus to elevated levels of corticosterone and its precursors, giving rise to secondary hyperaldosteronism with symptoms including hypertension, hypokalemia and fluid retention. As corticosteroids suppress ACTH, a low dose of prednisone must be administered with AA to control these adverse effects. In addition, it should be noted that abiraterone should be used with caution in patients with hepatic impairment and preexisting cardiac conditions (e.g., heart failure, recent myocardial infarction and atrial fibrillation). Hypokalemia and hypertension should be controlled before the start of the abiraterone therapy [62]. Abiraterone should be taken on an empty stomach and food should be avoided 2 h before and 1 h after taking it, as food intake affects its bioavailability. Patients on multidrug regimens should be screened for adverse drug interactions with abiraterone as it is metabolized by CYP3A4, which could be induced or inhibited by other therapeutic agents [63] (e.g., CYP3A4 inhibitors, such as azole antifungals and macrolide antibacterials; antiviral agents, such as, ritonavir, nelfinavir; and CYP3A4 inducers, such as carbamazepine, phenytoin, phenobarbital and rifampin) [62]. Cabazitaxel Cabazitaxel is a semisynthetic taxane which stabilizes microtubules. Unlike other taxanes, it has poor affinity for 3.4.2




P-glycoprotein efflux pump present at the cell membrane which mediates multidrug resistance [64,65]. It showed anticancer activity in preclinical models of both docetaxel-sensitive and -resistant cell lines [66]. In a Phase I clinical study to determine the preliminary evidence of anticancer and pharmacokinetic activities, cabazitaxel was given intravenously to 25 patients with advanced solid tumor malignancies at dose range of 10 -- 25 mg/m2. Based on the results from this study, 20 mg/m2 was selected for further Phase II study as neutropenia was the dose-limiting adverse effect [66]. Based on the results showing cabazitaxel efficacy in a Phase II study in breast cancer patients [67], a cabazitaxel dose of 25 mg/m2 was chosen for the Phase III trial (NCT00417079) in mCRPC patients. A total of 755 patients who had progressed during or after docetaxel treatment were randomly divided into two groups: prednisone 10 mg/day orally either with mitoxantrone 12 mg/m2 or cabazitaxel 25 mg/m2 and both agents were given intravenous on a 3-weekly cycle. Based on Response Evaluation Criteria in Solid Tumors (RECIST) and pain response, primary and secondary end points for this study were OS and PSA response, respectively. The median survival of 15.1 months (95% CI: 14.1 -- 16.3) was observed in cabazitaxel group as compared with 12.7 months (95% CI: 11.6 -- 13.7) in mitoxantrone group, conferring OS benefit to cabazitaxel. In addition, the median progression-free survival was longer in cabazitaxel group (2.8 months) as compared to mitoxantrone group (1.4 months). For cabazitaxel and mitoxantrone groups, the objective response rate was 14.4 and 4.4%, respectively [68]. Grade 3 and 4 hematological adverse effects such as neutropenia, leukopenia, anemia and thrombocytopenia are the main limitations of cabazitaxel use, as neutropenia was observed in 82 and 58% patients of cabazitaxel and mitoxantrone arm, respectively, with febrile neutropenic events in 8 and 1%, respectively. Other grade 3 or higher common toxicities due to cabazitaxel were fatigue, diarrhea, nausea and vomiting. It is associated with peripheral neuropathy such as other taxanes, paclitaxel and docetaxel. Therefore, dose adjustments should be made for prolonged neutropenia and growth colony-stimulating factors should be administered to the patients who are at increased risk of neutropenia [68]. The US FDA approved cabazitaxel use in combination with prednisolone for the treatment of CRPC after the failure of docetaxel therapy. It is administered as an intravenous infusion for 1 h every 3 weeks. Non-polyvinyl chloride materials and infusion sets should be used for the cabazitaxel dosage forms [62]. Enzalutamide As stated earlier in this review, overexpression, amplification and mutations in the AR gene confer resistance in hormoneresponsive prostate tumors. Therefore, enzalutamide (Figure 1) was developed as a high affinity AR inhibitor for the AR ligand-binding domain without any notable agonist activity. It showed 5- to 8-fold higher affinity than bicalutamide and 3.4.3

2- to 3-fold lesser affinity than natural ligands for AR in CRPC cells overexpressing AR in castrated mice. Owing to its irreversible binding to ligand-binding domain of AR, it inhibits AR nuclear translocation, DNA-binding and coactivator recruitment leading to growth suppression and apoptosis [69]. Therefore, a Phase I/II clinical trial of enzalutamide was started with a primary objective to determine its safety and tolerability in 140 mCRPC patients. The criteria for its antitumor effects were decrease in PSA, soft tissue response using the RECIST and stabilization of osseous disease. Enzalutamide was rapidly absorbed achieving maximum plasma concentration between 30 min and 4 h. It has a half-life of 1 week which is not affected by starting dose, and steady state was attained after 1 month. The maximum tolerable dose was determined to be 240 mg/day as greater doses did not show enhanced antitumor effects. More than 50% decrease in PSA levels was observed in 78 of 140 (56%) patients from all cohorts, irrespective of patients with or without previous chemotherapy or number of hormonal therapies. No disease progression was observed in 49% patients, while median time to radiologic progression was 47 weeks in 22% patients. In addition, 56% patients showed stability in bone disease for ‡ 12 weeks [70]. Owing to these encouraging results, a Phase III, randomized, double-blind, placebo-controlled study called AFFIRM (a study evaluating the efficacy and safety of the investigational drug MDV3100) was conducted in mCRPC patients who were previously treated with one or two prior chemotherapy regimens, including docetaxel. A total of 1199 patients were enrolled and randomly divided into two groups, either receiving placebo or 140 mg of enzalutamide. OS was set as the primary end point for this trial, whereas secondary end points were PSA response, objective soft tissue response or progression per RECIST, quality-of-life response as measured by Functional Assessment of Cancer Therapy-Prostate, progression of osseous disease and death from any cause. An improvement in the median OS was observed in the enzalutamide arm (18.4 months; 95% CI: 17.4 to not yet reached) compared to the placebo arm (13.6 months; 95% CI: 11.3 to 15.8). Multivariate analysis of the data with adjustment for baseline prognostic factors demonstrated 37% increase in OS (hazard ratio = 0.63; 95% CI: 0.53 to 0.75; p < 0.001) in all subgroups treated with enzalutamide. Therefore, AFFIRM trial was halted due to successful fulfillment of preset interim efficacy stopping criteria and favorable risk to benefit ratio for enzalutamide. Based on these results, the trial Independent Data Monitoring Committee recommended that the patients in the placebo arm should also be treated with enzalutamide. The most commonly observed adverse effects were fatigue (34%), diarrhea (21%), hot flashes (20%), musculoskeletal pain (14%) and headache (12%) [71,72]. Notably, 5 of 800 patients in the enzalutamide group versus none in the placebo group developed seizures which eventually resolved with discontinuation of therapy.


17


These encouraging results led to the US FDA approval on 31 August 2012 of enzalutamide 160 mg/day to be taken orally for the treatment of CRPC in patients previously treated with docetaxel. Presently, multiple Phase III clinical trials are being conducted for enzalutamide including PREVAIL trial for chemo-naı¨ve mCRPC patients (NCT01212991), compared to bicalutamide (NCT01664923, NCT01288911), in combination with docetaxel (NCT01565928), and in combination with abiraterone (NCT01650194) [61,72]. Selected agents in Phase III clinical trials It is also worth mentioning promising anti-prostate cancer agents such as cabozantinib and custirsen that are in Phase III clinical trials. Cabozantinib is an orally bioavailable receptor tyrosine-kinase inhibitor [73] that specifically inhibits hepatocyte growth factor c-Met and the vascular endothelial growth factor receptor 2. In a Phase II, randomized discontinuation trial, cabozantinib showed clinical activity by improving progression-free survival, reducing soft tissue lesions and reducing bone turnover markers, as well as pain and narcotics use in CRPC patients [74]. These and other promising observations led to two Phase III clinical trials namely COMET-1 (NCT01605227) and COMET-2 (NCT01522443). The antisense oligonucleotide custirsen targets the chaperone protein clusterin that is involved in ADT, chemotherapy and radiotherapy resistance [75]. Efficacy shown by custirsen in Phase I and Phase II clinical trials prompted various Phase III clinical trials such as SYNERGY and AFFINITY in CRPC patients [75].


3.4.4

4.

Conclusion

Prostate cancer treatment is very complex, but recent advances in the understanding of the molecular biology of this disease have led to the discovery of more specific, advanced agents for its treatment. New anti-prostate cancer agents including, but not limited to, abiraterone, cabazitaxel and enzalutamide have shown significant therapeutic potential by improving duration and quality of life in prostate cancer patients. However, understanding the mechanisms of primary and secondary resistance remains a great challenge for future prostate cancer drug design and discovery efforts. Thus, combinations of multiple therapeutic agents, as well as a rational approach to sequencing their administration, coupled with the discovery of potential new biomarkers, might hold the key for the future of prostate cancer therapy. 5.

Expert opinion

In this review, we have discussed three novel agents that are now approved by FDA for mCRPC patients with (cabazitaxel, enzalutamide and abiraterone). Although out of the scope of our review, two additional agents were also recently approved for metastatic prostate cancer: sipuleucel-T in April 2013 and radium-223 in May 2013. Both of these agents are associated with a median OS benefit on the order of 4 months, 18

similar to the other drugs discussed in this review. Owing to these remarkable advances, mCRPC patients now have many therapeutic options. What are the principles that can be used by patients and medical oncologists to make these decisions? First and foremost, agents that prolong survival are preferred if there are no contraindications or patientspecific characteristics that would indicate otherwise. For that reason, mitoxantrone, which palliates pain but does not prolong survival, is no longer a preferred second-line agent for mCRPC patients. The same is true of secondary hormonal agents which have never been shown to improve survival in patients with prostate cancer. Unfortunately, head-to-head comparisons between these novel agents are largely lacking, making treatment decisions more difficult. Of note, enzalutamide, abiraterone, sipuleucel-T and radium-223 were compared to prednisone or placebo in their respective Phase III registration studies, while docetaxel and cabazitaxel were compared to mitoxantrone. In the absence of direct comparative data, treatment decisions are largely determined by toxicity profile and a clinical judgment about the likelihood of benefit and response. Eligibility criteria for the respective trials can also be used to select an appropriate patient population that would be expected to benefit from a particular therapy. To a lesser degree, clinical decisions may be influenced by financial issues, given the significant expense of these novel therapies. Reimbursement for intravenous versus oral drugs can vary dramatically and in either situation, the full cost is not always covered, even for insured patients. When a course of therapy with any novel agent approaches or exceeds $100,000, even small co-pays can be out of most patients’ financial reach. To illustrate which patient populations are currently considered suitable for particular therapies, a mCRPC patient who is asymptomatic and chemotherapy-naı¨ve, would currently qualify for treatment with sipuleucel-T and abiraterone. These therapies may be sequenced, or some patients may prefer oral therapy over intravenous. Some patients and practitioners may also be dismayed that there is no PSA or radiographic response associated with sipuleucel-T. Currently, there is insufficient data to recommend treatment with enzalutamide in the pre-chemotherapy setting, but results of a Phase III clinical trial to answer that question are expected in 2013. Docetaxel could also be considered, but an asymptomatic patient may not be amenable to undergo the expected burden of additional toxicity from cytotoxic chemotherapy. Nonetheless, docetaxel should be considered for the asymptomatic patient if the patient is showing signs of rapid progression or soft tissue/visceral metastases. Further, patients with poor performance status (ECOG ‡ 2) and visceral metastases were not included in the clinical trials, demonstrating benefit for abiraterone prior to chemotherapy and sipuleucel-T and thus these patients may not be ideal candidates to benefit from either abiraterone or sipuleucel-T. It is also interesting to speculate whether prior poor response to hormone therapy would predict a similar poor response to




abiraterone, but such data is currently lacking. The development of clinical, molecular or other predictive markers of treatment response would dramatically improve the ability of clinicians to choose appropriate treatment. The on-label use of enzalutamide is currently reserved for patients who have already been treated with docetaxel. However, Phase I/II data suggest significant activity in the pre-chemotherapy setting and final results of a pivotal Phase III trial are expected in late 2013 (NCT01212991). The design of this study is very similar to the analogous abiraterone study, with a placebo comparator and a minimally symptomatic patient population. The primary comorbidity which would limit treatment with enzalutamide is a predisposition to seizures, as it appears that enzalutamide, and potentially other drugs in this class, may lower the seizure threshold. As is true universally in prostate cancer, there are no predictive markers of treatment response. Similarly, cabazitaxel is only indicated for patients who have failed docetaxel therapy; however, studies investigating its use earlier in the course of disease are ongoing (NCT01308567). Cabazitaxel has a similar toxicity profile and mechanism of action as docetaxel and should be used with caution in the elderly and those with significant comorbidities. Of note, myelosuppression from cabazitaxel can be severe, especially in heavily pretreated patients, and appropriate precautions should be taken to treat and prevent neutropenic sepsis. Using a dose of 20 mg/m2 may be appropriate in some patients. In addition, renal and GI toxicities should be monitored closely. Although confirmatory data are lacking, there is some evidence from the TROPIC study that patients who had a greater cumulative exposure to docetaxel had more benefit from cabazitaxel, thus suggesting that patients who respond well to therapy may again do well with treatments that share a similar mechanism of action. As the toxicity profiles of abiraterone, enzalutamide and cabazitaxel differ, selection of any of these agents depends on patient assessment (e. g., patients with seizure disorder may be prescribed cabazitaxel over enzalutamide). In addition, organ function should be assessed to avoid exacerbating underlying conditions or causing excessive toxicity (e.g., enzalutamide may be preferred in patients with moderate hepatic dysfunction since cabazitaxel is metabolized in the liver and abiraterone may cause hepatic toxicity). Currently, all of these novel agents (abiraterone, enzalutamide, cabazitaxel and sipuleucel-T) are only indicated in the setting of castrate-resistant metastatic disease. There is significant clinical interest to expand treatment indications to patients who have castrate-sensitive disease, biochemicalonly disease and high-risk localized disease. Studies to address

these issues are currently ongoing. In the absence of metastatic disease, minimizing toxicity from treatment becomes paramount. For example, a patient who may be cured by radiation or surgery alone would rightly be cautious about accepting a therapy which significantly increases long-term toxicity. For this reason, and because benefit in these settings is still unproven, treatment with these agents in the setting of biochemical recurrence or in the adjuvant setting would still be considered experimental. Prostate cancer is a heterogeneous disease at both the molecular and therapeutic levels; however, due to recent advances in the understanding of the molecular biology of prostate cancer, the number of in-development drugs and US FDA-approved drugs is steadily increasing. Importantly, most of these agents have different mechanisms of action, which should reduce the risk for cross-resistance. Unfortunately, a lack of comprehensive comparison data for many of these new, as well as established, anti-neoplastic agents warrants further in-depth studies and clinical trials. The advent of new drugs for prostate cancer also underscores the multidisciplinary approaches to effectively treat the disease, and as the incidence of prostate cancer increases with age, polypharmacy in elderly patients should be taken into account when designing combination therapies. Comprehensive patient assessment should be performed when designing clinical trials as well as treatment strategies, as drugs which are used in treating other conditions (e.g., high blood pressure) might affect the bioavailability of anti-prostate cancer agents. Appropriate timing and sequencing of combination strategies are still key unresolved issues in the field of prostate cancer treatment, and keeping in mind that many patients eventually progress, as well as the modest survival benefit of anti-prostate cancer drugs, further research in identifying resistance mechanisms is warranted. Identification of new biomarkers as well as more relevant clinical trial end points may hold the key for the future of prostate cancer therapy and the data obtained from clinical trials will help in identifying these new biomarkers, as well as molecular drivers and therapeutic agents for prostate cancer.

Declaration of interest The authors declare no conflicts of interest. This work has been partially supported by NCI R01 CA127258 (to Qing Ping Dou), NIH center grant P30 CA022453 (to Karmanos Cancer Center) and Thomas C. Rumble Fellowship from Wayne State University (to Rahul Deshmukh and Sara M Schmitt). C Hwang has no conflicts of interest.


19


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Affiliation Rahul R Deshmukh1, Sara M Schmitt2, Clara Hwang5 & Qing Ping Dou†1,2,3,4 † Author for correspondence 1 Wayne state University, Karmanos Cancer Institute, School of Medicine, Department of Pathology, 540.1 HWCRC, 4100 John R Road, Detroit, MI 48201, USA 2 Wayne State University, Karmanos Cancer Institute, School of Medicine, Department of Oncology, Detroit, MI 48201-2013, USA 3 Wayne State University, Karmanos Cancer Institute, School of Medicine, Department of Pharmacology, Detroit, MI 48201-2013, USA Tel: +1 313 576 8301; Fax: +1 313 576 8307; E-mail: [email protected] 4 Wayne State University, Karmanos Cancer Institute, School of Medicine, Detroit, MI 48201-2013, USA 5 Henry Ford Hospital, Josephine Ford Cancer Center, Division of Hematology/Oncology, Department of Internal Medicine, Detroit, MI 48202, USA

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