Tyrosine kinase inhibitors in the treatment of prostate cancer: taking the next step in clinical development.

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Review

Tyrosine kinase inhibitors in the treatment of prostate cancer: taking the next step in clinical development

1.

Background

2.

Medical need

3.

Existing treatment

Michelle A Ojemuyiwa, Ravi A Madan & William L Dahut†

4.

Current research goals

†

5.

Scientific rationale

6.

Competitive environment

7.

Anti- EGFR TKIs

8.

Platelet-derived growth factor receptor

9.

Src family kinases

10.

VEGF pathways

11.

c-Met

12.

Potential development issues

13.

Conclusion

14.

Expert opinion

National Cancer Institute, Medical Oncology Branch, Bethesda, MD, USA

Introduction: Prostate cancer (PCa) is the most frequently diagnosed, non-cutaneous malignancy in Western countries. Until recently, few therapeutic options were available for patients with advanced PCa. Although these treatments may delay progression of disease, none are curative. Therefore, research continues to investigate other treatments for advanced PCa. Tyrosine kinase inhibitors (TKIs) have been extensively studied as a treatment for multiple malignancies and may represent an additional strategy. In addition to limiting cellular proliferation and metastasis, there is also growing interest in using these treatments to impact the bone microenvironment and reduce associated morbidity from PCa. Areas covered: Several TKIs have been evaluated in the preclinical setting in advanced PCa. Targets reviewed include the epidermal growth factor family, VEGF receptor, c-Src family kinases, platelet-derived growth factor and c-Met. Expert opinion: Despite strong biological rationale for the use of TKIs therapy for the treatment of PCa, Phase III clinical trials have produced disappointing results. As TKI strategies move forward, the failures of past trials need to be better understood. New approaches with these treatments will also have to take into account modern anti-androgens and a treatment landscape that now includes immunotherapy. Keywords: castrate-resistant metastatic prostate cancer, c-Src family kinases, EGFR, plateletderived growth factor, prostate cancer, tyrosine kinase inhibitor, VEGF Expert Opin. Emerging Drugs [Early Online]

1.

Background

Prostate cancer (PCa) is the most frequently diagnosed, non-cutaneous malignancy in men in Western countries. In the United States, PCa represents the second leading cause of cancer-related death with 233,000 new cases and 29,480 deaths estimated in 2014 [1]. Approximately, one in every six men will be impacted by PCa with the median age at diagnosis of 67 years [2]. PCa is more prevalent in developed countries where the use of prostate specific antigen (PSA) testing has played a significant role in dramatically increasing PCa incidence. Serum PSA testing became common as PCa screening tool more than two decades ago with the goal of increasing more localized and hence more curable disease, thereby reducing advanced disease and the associated morbidity and mortality [3,4]. Although earlier detection has led to increased curability of localized disease, some patients still present with metastatic disease, and up to 40% of patients treated with curative intent will experience disease recurrence [5]. For locally advanced or metastatic disease, suppressing tumor growth by medical hormone ablation or surgical castration remains the mainstay of treatment [6]. However, the typical response to androgen deprivation therapy (ADT) is 1 -- 2 years, after which time the disease is 10.1517/14728214.2014.969239 © 2014 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted

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M. A. Ojemuyiwa et al.

likely to grow (as measured by PSA or radiographic findings) in spite of castration levels of testosterone [7,8]. Once, the disease progresses to metastatic castration-resistant prostate cancer (mCRPC) disease-related symptoms significantly increase. Until recent years, treatment with the chemotherapeutic agent docetaxel represented the standard firstline treatment for symptomatic mCRPC, but now there are many effective therapies often with less side effects that are able to prolong survival in patients [9]. While this represents a significant step forward in the treatment of mCRPC, these new therapeutics only delay progression and additional interventions are necessary to mitigate the morbidity and mortality associated with metastatic disease. Targeting tyrosine kinase activity with molecular inhibitors has been extensively studied in multiple solid tumors and may represent another therapeutic option in mCRPC.

focus of multiple clinical trials. In addition, supportive agents such as zolendronic acid and deonsumab have decreased the morbidity from skeletal-related events from PCa [18,19]. It is remarkable that each of these agents has a different mechanism of action, and thus, it may be possible that a tyrosine kinase inhibitors (TKIs) may yet be added to this list. A more recent development is noteworthy in a subset of patients with castration sensitive, metastatic disease. Although such patients make up only 5 -- 10% of the population of metastatic PCa patients, those with high-volume metastatic disease experienced a statistically significant OS benefit of 17 months when treated with chemohormonal therapy (ADT combined with docetaxel; 49.2 vs 32.2 months; HR = 0.60) [20]. These findings have once again highlighted the potential benefit of cytotoxic chemotherapy in PCa. 4.

2.

Although there is decreased mortality with localized PCa, metastatic disease remains incurable. This is due to the development of castration-resistant disease in which patients with CRPC historically have very poor survival. The addition of anti-androgens and other therapeutics in the post chemotherapy setting only result in prolonging survival, emphasizing the unmet need for novel therapeutics. 3.

Existing treatment

Even with the strong scientific rationale for many TKIs in the treatment of PCa, the clinical trial experience to this point has been underwhelming with a litany of negative trials. Based on this experience, the current goals are to better understand the failures of previous trials so that future trials may better utilize these targeted therapies to improve outcomes in PCa. In order to move forward, it is best to try and understand the therapeutic targets, clinical design and outcomes of previous trials. 5.

ADT is the mainstay of treatment for patients with castrationsensitive metastatic PCa with low tumor burden. The initial response rates are 80 -- 90%. Regardless of this, virtually all men with metastatic disease will progress to CRPC [10]. Experimental evidence has shown that continued androgen receptor (AR) signaling remains essential in the progression of CRPC. Several proposed mechanisms have been implicated in the development of CRPC including amplification of AR, activating mutations leading to constituent AR activity, secondary production of androgens from the tumor itself, and additional AR bypass mechanisms [11]. Once CRPC develops, the responses to second-line treatment with alternative hormonal therapy or chemotherapies are limited with a median overall survival (OS) of ~ 30 months [8,12]. In 2004, docetaxel with prednisone (when compared with mitoxantrone and prednisone) became the first chemotherapy agent to demonstrate extended survival for men with mCRPC (18.9 vs 16.5 months; p = 0.009, hazard ratio [HR] = 0.76) [9]. In recent years, five additional therapies have been approved by the FDA based largely on survival benefit in mCRPC. These treatments include cabazitaxel (second-generation taxane) [13], enzalutamide (AR antagonist) [14], sipuleucel-T (therapeutic cancer vaccine) [15], abiraterone (CYP17 lyase inhibitor) [16] and radium 233 (bone-seeking radiopharmaceutical) [17]. The optimal combination and sequence of these agents are currently the 2

Current research goals

Medical need

Scientific rationale

Growth factors stimulate proliferation, support survival and enhance migration and invasion of PCa cells [21]. TKIs are small drug molecules that work by competitive ATP inhibition at the catalytic binding site of tyrosine kinase. This results in complete inhibition of the catalytic activity of certain enzymes. If chosen correctly, TKIs can target and inhibit critical, mutated pathways important for the development, progression and metastasis of PCa [22]. Agents that target kinases associated with development and progression of malignancy have seen remarkable success in some cancers and have been extensively evaluated in PCa. Table 1 lists some rationales for each receptor tyrosine kinase reviewed here. 6.

Competitive environment

The results of the ongoing and completed trials are discussed in Table 1. EGFR pathways The EGFR is included in the ERBB transmembrane growth factor receptor family. This is a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/ c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4) [23]. ErbB receptors are expressed in a wide array of tissues where they have critical roles in cellular proliferation and 6.1

Expert Opin. Emerging Drugs (2014) 19(4)

Tyrosine kinase inhibitors in the treatment of prostate cancer

Table 1. Scientific rational for each tyrosine kinase.


Receptor inhibited

Agent

EGFR

Erlotinib Gefitinib

HER2 Nu/EGFR

Lapatinib

PDGFR

Imatinib

Dual kinase inhibitor Abl and Src kinases

Dasatinib

VEGFR

Cediranib Sorafenib Sunitinib

c-Met and VEGFR-2

Cabozantinib

Scientific rationale in prostate cancer EGF, ligand for EGFR, plays a regulatory role in the proliferation of PCa cells and in tumor angiogenesis [98] EGF can display androgen-independent activation in PCa cell lines [99] in vitro studies proved that inhibiting EGFR could reduce chemo-migration of human PCa cell lines [98] HER-2 expression promotes tumor growth of prostate xenografts in castrated animals and heightens ligand-independent activation of AR through tyrosine phosphorylation of AR protein Inhibition of HER-2 kinase results in inhibition of prostate xenograft tumor growth and decreases AR transcriptional activity [100] EGFR and HER-2 combined may activate additional down-stream to promote tumor cell proliferation and survival PDGFR is overexpressed in bone metastasis of PCa [46] PCa cells also express the receptor ligand platelet-derived growth factor, a known mitogen for osteoblasts [101] Over expression of Src and AR in murine prostate models results in development of poorly differentiated PCa [102] Constitutively, active SFK members exhibit differential oncogenic potential in primary prostate cells [103] Selective loss of SFKs differentially inhibit paracrine FGF10-induced PIN and carcinoma [104] Microvessel density was reported to be substantially higher in PCa samples from patients with metastatic disease when compared with those without metastatic disease [66] Elevated plasma and urine levels of VEGF-A was found to be associated with metastatic progression and reduced survival in patients with PCa. VEGF have been implicated in disease progression [70] In addition to VEGF properties, upregulation of c-Met sensitized it to its ligand hepatocyte growth factor stimulation and resulted in increased cell motility and invasiveness of PCa [105]

AR: Androgen receptor; EGF: Epidermal growth factor; PCa: Prostate cancer; PDGFR: Platelet-derived growth factor receptor; SFK: Src family kinase.

differentiation. The ErbB receptors are activated by multiple ligands including heregulins (HRG, human) and neuregulins in addition to other epidermal growth factor-like ligands [24]. Homodimerization is required for stimulation of EGFR, but under certain conditions, heterodimerization with other family members may occur to stimulate intrinsic tyrosine kinase activity [25,26]. Activation of the EGFR pathway enables cellular maturation, proliferation, invasion, resistance to apoptosis and angiogenesis resulting in tumor growth and progression (Table 2) [23,27,28]. EGFR is frequently over expressed in human tumor types and can be an important therapeutic target. In PCa, immunohistochemistry reported increased frequencies of EGFR expression, although with great variability [29]. One study completed by Schlomm et al. looked at 2497 PCa patients on the DNA level where detectable EGFR was expressed in 18% of cases. EGFR over expression was associated with higher grade tumors, more advanced stage and shorter disease progression-free survival (PFS) [29]. Preclinical data suggest that EGFR signaling pathways may activate the AR, enhancing a receptor-mediated cancer growth, particularly in the setting of ADT. One study completed by Schlomm et al. looked at 2497 PCa patients where detectable EGFR was expressed in

18% of cases. In the evaluation, EGFR over expression was associated with higher grade tumors, more advanced stage and shorter disease PFS [29]. Preclinical data also suggest that EGFR signaling pathways may activate the AR, enhancing a receptor-mediated cancer growth, particularly in the setting of ADT. These findings highlight the potential significance of this target. 7.

Anti- EGFR TKIs

Several studies have evaluated gefitinib in the mCRPC setting. A Phase II trial that evaluated gefitinib in advanced PCa failed to demonstrate PSA declines or clinical responses when given as monotherapy [30,31]. A Phase II study with gefitinib combined with the chemotherapy agent docetaxel evaluated 37 men with CRPC. The most common adverse events (AEs) were diarrhea, stomatitis, fatigue, alopecia, dysgeusia and vomiting. Although seemingly well tolerated, the results demonstrated that the combination did not improve OS or PFS compared to docetaxel alone [32]. Erlotinib is also a selective TKI of EGFR and is currently FDA approved for treatment of pancreatic cancer in combination with gemcitabine, as well as second-line therapy for


3


Table 2. Competitive environment. Target

Compound

EGFR

Erlotinib

Genentech

Gefitinib Lapatinib Imatinib

AstraZeneca GlaxoSmithKline Novartis

Sunitinib Cediranib

Pfizer AstraZeneca

Src

Sorafenib Dasatinib

MET

Cabozantinib

Bayer Bristol-Myers Squibb Exelixis


Her2 Platelet-derived growth factor receptor VEGFR

Company

NSCLC. A Phase I study of single agent erlotinib evaluated 29 patients with mCRPC [33]. The primary end points included overall response and secondary end points included time to progression, OS, PSA responses and doubling time. Of the 22 evaluable patients, there was an overall response rate of 31%. PSA doubling time also improved from 3 months to 6 months. Results concluded that erlotinib single agent may have moderate activity against mCRPC. Although Phase I studies demonstrated modest activity in mCRPC, combination Phase II studies of erlotinib and chemotherapy were underwhelming and failed to show significant activity in PCa. In a study, 22 patients with mCRPC were treated with combination therapy with erlotinib and docetaxel [34]. Of the 22 patients, 23% had a > 50% decline in PSA. Hematologic toxicity included grade 3 neutropenia in 40% of patients and neutropenic fever in 9% of patients. Common non-hematologic toxicities (‡ grade 3) included fatigue, anorexia and diarrhea. There was no response by resist criteria was seen in the study. Lapatinib, a dual TKI of both EGFR and HER-2, is currently approved for the treatment of HER-2-positive metastatic breast cancer. HER2 has been studied as potential target in PCa. Expression of HER-2 promotes tumor growth of prostate xenografts in castrated animals and enhances ligandindependent activation of AR through tyrosine phosphorylation of AR protein [35-37]. A Phase II study using single agent lapatinib evaluated 29 chemotherapy-naive CRPC patients, with median age of 73 years and a baseline PSA of 21.6 ng/ml. The primary end point of the study PSA was a decline of 50%. The dose of 1500 mg daily of lapatinib was given until progression. Seven patients had no radiologic evidence of metastatic disease, while the remaining patients had bone or measurable disease or both (mCRPC). Treatment-related toxicities included grade 3 diarrhea (14%) and rash (3%). One of 21 evaluable patients had 50% reduction in PSA. The 4

Indication

CRPC, CRPC, CRPC, CRPC, CRPC,

chemotherapy-naı¨ve chemotherapy naive chemotherapy naı¨ve chemotherapy naı¨ve chemotherapy naı¨ve

Phase in development

Results

Phase Phase Phase Phase Phase

II II II II II

Promising Negative Negative Negative Negative

mCRPC CRPC mCRPC CRPC mCRPC

Phase Phase Phase Phase Phase

III I II III III

Negative Negative

mCRPC, chemotherapy-naive mCRPC

Phase I Phase II

Ongoing positive

Negative Negative

median time to PSA progression was 29 days. Lapatinib showed single-agent activity only in a very small subset of unselected patients with castration-resistant PCa based on PSA decline [38]. 8.

Platelet-derived growth factor receptor

Platelet-derived growth factor (PDGF) was initially discovered as a mitogen of vascular smooth muscle cells. PDGF are members of a family of four distinct polypeptides encoded by four different genes [39,40]. The identified subunits include PDGF-A, PDGF-B, PDGF-C and PDGF-D [41]. It is a dimeric glycoprotein that either consists of two homodimers of each subunit, or one heterodimer PDGF-AB. Platelet-derived growth factor receptor (PDGFR) is the receptor for PDGF and is classified as a receptor tyrosine kinase. Two receptors have been identified, a and b type PDGFR. Activation of the receptor by PDGF leads to receptor dimerization, which causes autophosphorylation. This leads to downstream activation of multiple signaling pathways including the PI3K pathway and the STAT3 pathway, which play roles in embryonic development, cell proliferation, cell migration and angiogenesis [42-45]. Over expression of PDGFR has been described in several malignancies. In PCa, over expression of PDGFR has been observed in both primary and metastatic sites by immunochemical staining analysis [46]. In one study, amplification of conserved domains of tyrosine kinase receptors using degenerate primers identified a-PDGFR as the most commonly amplified transcript in PCa bone metastases [47]. Imatinib Imatinib mesylate, a phenylaminopyrimidine derivative, is a TKI of the receptors for Bcr-Abl, c-Kit and PDGFR [48]. Originally developed for targeting the fusion kinase Bcl-Abl, which plays a central role in chronic myelogenous leukemia, 8.1




there have been several studies that have evaluated imatinib for the treatment of mCRPC. A Phase I study was conducted in men with CRPC with the combination of imatinib and zoledronic acid with the primary objective to determine the safety and efficacy of the combination in patients with bone pain. Fifteen patients were treated with zoledronic acid 4 mg intravenously every 28 days and imatinib mesylate 400 mg/day. None of the evaluable patients met criteria for pain response, analgesic medication reduction, PSA response or radiographic responses [49]. A modular Phase I combination trial with docetaxel in men with mCRPC (including bone metastasis) attempted to capitalize on preclinical observations suggesting PDGFR inhibition with imatinib can be effective in PCa. Twentyeight men with mCRPC were enrolled to receive imatinib 600 mg daily lead-in for 30 days, then imatinib 600 mg daily and one of six possible doses of docetaxel weekly for 4 weeks. During the lead-in period with imatinib alone, 7% of patients showed a decline in PSA levels of 50%, whereas 89% showed a progression in PSA levels. Twenty-one patients were treated with the imatinib/docetaxel combination therapy; of these, 38% had a > 50% decline in PSA levels, 29% had a PSA decline < 50% and 33% had PSA level progression. These results suggest that treatment with the combination of imatinib and docetaxel reduces PSA levels with greater efficacy than 1 month of imatinib alone (67 vs 7%, respectively). A decline in PDGFR-expressing tumor was seen in serial bone biopsies with the combination therapy but not with imatinib alone. These results suggest that combination therapy that includes PDGFR inhibition is feasible and may have therapeutic value [50]. A follow up-Phase II randomized study involving 144 patients with mCRPC imatinib and docetaxel versus docetaxel alone, had disappointing results with no significant difference between progression among the two groups (median progression of 4.2 months in both groups) [51]. Furthermore, accrual was halted early because of adverse gastrointestinal events. The clinical results of both monotherapy and combination therapy with imatinib call into question the efficacy of PDGFR targeting as a potential therapeutic option in mCRPC. 9.

Src family kinases

Src family kinases (SFK) are non-receptor tyrosine kinases and have been evaluated in several malignancies. They are the largest family of no receptor protein tyrosine kinases and are responsible for signal transduction during many cellular activities, including, adhesion, differentiation and migration [52]. There are nine members of the SFK (Blk, Fgr, Fyn, Hck, Lck, Lyn, Src, Yes and Yrk). c-Src is made up of six functional regions: Src homology (SH) 4 domain (SH4 domain), unique region, SH3 domain, SH2 domain, catalytic domain and short regulatory tail. It can be activated by many transmembrane proteins that include: adhesion receptors, receptor

tyrosine kinases [52], G-protein-coupled receptors and cytokine receptors. There is evidence that implicates aberrant Src/SFK activity in cancer development. Src, Lyn and Fyn, are highly expressed in PCa cells, compared to normal cells. Src signaling is involved in androgen-induced proliferation of PCa. Several studies demonstrated that Src inhibitors decreased the proliferation, invasion and migration of PCa cell lines in vitro [53-56]. Src inhibitors also reduced PCa growth and metastasis in mouse xenograft studies. Fyn, which can be overexpressed in PCa, can affect prostate cell proliferation and chemotaxis especially in response to hepatocyte growth factor (HGF), a growth factor in the bone microenvironment [57]. Dasatinib Dasatinib is a multi-kinase inhibitor that inhibits SFK members and BCR-ABL and is currently approved for treatment of chronic myelogenous leukemia [58]. In preclinical models, dasatinib was able to inhibit actions of Src, and Lyn, kinases in PCa cell lines at low levels [59]. Dasatinib has demonstrated activity in inhibiting PCa metastasis as well as suppression of PCa cell-induced osteoclastic activity in preclinical models [60-62]. Inhibition of these kinases results in suppression of cell adhesion, migration and invasion [61]. This data provided the rationale to evaluate dasatinib as treatment for PCa. The READY trial, a Phase III, double-blind randomized controlled trial that evaluated men with chemotherapy-naive mCRPC who were randomized to receive docetaxel plus prednisone with either dasatinib or placebo [63]. Primary end points were OS, which were comparable amongst the two groups with OS of 21.5 months with dasatinib and 21.2 months with placebo (HR = 0.99). Secondary end points included PSA progression (HR = 0.89), PFS (HR = 0.92), time to first skeletal event (HR = 0.81) and objective response (HR = 0.94), all which did not demonstrate clinical benefit. The most common grade 3 -- 4 AEs included diarrhea (8% of patients in the dasatinib group vs 4% patients in the placebo group), fatigue (8 vs 6%, respectively) and asthenia (5 vs 3%, respectively). Overall, the addition of dasatinib to docetaxel did not improve OS in mCRPC chemotherapynaive men and potentially added toxicity to standard chemotherapy. 9.1

10.

VEGF pathways

VEGF is a key angiogenic factor and has been vital regulator of both normal and pathologic angiogenesis. Over expression of VEGF has been linked to many malignancies and inhibition of angiogenic pathways and has proven an effective method for the treatment of certain solid tumors [64]. A potent mitogen of angiogenesis, VEGF plays a major role in regulating normal embryonic vasculogenesis, and migration and induction of proteinases leading to remodeling of the extracellular matrix, increased vascular permeability and


5



maintenance of survival for newly formed blood vessels [65]. All members of the VEGF family stimulate cellular responses by binding to tyrosine kinase receptors (the VEGFRs) on the cell surface. The most notable receptors are VEGFR-1 (flt-1), and VEGFR-2 (KDR/flt-1). VEGF plays a critical role in the pathogenesis and progression of human PCa [66,67]. Increased AR signaling has been linked to a dose-dependent increase of messenger RNA of VEGFR 1 and 2 [68]. Correlation of microvessel density, a surrogate measure of tumor angiogenesis, and gleason score in PCa can be predictors of disease progression [66,69]. Duque et al. described an association between elevated urine levels of VEGF-A and metastatic progression, which correlated in reduced survival in patients with PCa [70]. These findings encouraged studies of anti-antigenic treatments in mCRPC. At the forefront was bevacizumab, a humanized monoclonal antibody developed to bind soluble VEGF and thereby limit tumor neovascularization. The CALGB Phase III trial was a randomized controlled study where docetaxel, prednisone and bevacizumab were compared with docetaxel and prednisone alone in 1050 men with chemotherapy-naive mCRPC [71]. Although the addition of bevacizumab led to significant improvements in PFS, and PSA response, there was no change in OS. Several different multitargeted TKIs with anti-VEGF properties have also been evaluated in mCRPC.

Sunitinib Sunitinib is an oral multitarget TKI which inhibits the receptor tyrosine kinase activity of VEGFR as well as other kinases, including PDGFR and KIT [72,73]. Sunitinib is approved for use in metastatic renal cell cancer, where it has been shown to significantly improve PFS [74]. Toxicities include hypertension, similar to other VEGF inhibitors. A Phase II study was conducted using single-agent Sunitinib in men with mCRPC (n = 36) who had progressed after chemotherapy displayed activity. This trial used non-PSA-based clinical determinants to include radiologic progression, with the primary objective being to determine whether sunitinib therapy was associated with a clinical PFS of 12 weeks in > 30% of patients. The median PFS was 19.4 weeks with the 12-week PFS being 75.8%. In the study, 12.1% of subjects had a > 50% decline in PSA, with 11% having a 30% decline in measurable disease by RECIST criteria. However, sunitinib caused severe drug reactions, as half of the patients had to withdraw secondary to toxicity [75]. Nonetheless, this treatment demonstrated promise in this small study and alternative strategies have been explored to use lower dosing to minimize the toxicities. A Phase III randomized controlled study of sunitinib plus prednisone versus placebo plus prednisone evaluated men with mCRPC status postchemotherapy with docetaxel or intolerant to chemotherapy. Unfortunately, this study demonstrated no OS advantage when compared to the experimental arm [76]. 10.1

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Sorafenib Sorafenib is an oral TKI that targets the Ras/Raf kinase pathway, vascular endothelial growth factor and PDGFR [77,78]. It is currently approved by the FDA for treatment of renal cell and hepatocellular cancer [78,79]. Phase II studies investigating sorafenib monotherapy in mCRPC have demonstrated modest activity with some discordance between PSA and radiological responses. Of note, sorafenib was shown to increase PSA production on a per cell basis despite a potential antitumor effect, highlighting the need to be cautious when interpreting PSA responses when using TKIs [80]. With this in mind, a study evaluated 24 patients (21 of whom had previously progressed on docetaxel) dosing sorafenib at 400 mg twice a day, using only radiographic progression as an end point. The median PFS in this population was 3.7 months with a median PFS of 18 months. Common toxicities included palmar-plantar erythrodysesthesia, rash and fatigue [81]. 10.2

Cediranib Cediranib is an antiangiogenic TKI that inhibits both VEGF-1 and VEGF-2 [82]. In PCa animal models, cediranib demonstrated improvement in OS, as well as delaying metastasis [83]. A Phase I study evaluated the maximum-tolerated dose in men with metastatic castration-resistant PCa at 20 mg daily due to development of grade 3 fatigue, hypertension and muscle weakness at the 30 mg dose [84]. Of the 26 patients involved in the study, only 19 were able to be evaluable after completing at least 28 days of therapy. None of the patients achieved a > 50% decline in PSA while on therapy; however, upon discontinuation of treatment several patients had substantial PSA declines suggesting that the treatment artificially elevated PSA in some patients. A Phase II study was completed using cediranib in postdocetaxel mCRPC patients. Of the 59 patients enrolled in the study, 39 patients had measurable disease, with an overall objective response rate of 18%. The median PFS was 3.7 months, whereas median OS was 10.1 months. Toxicities included fatigue, muscle weakness and hypertension [85]. Currently, there is a Phase II trial ongoing, randomizing combination cediranib with or without dasatinib in patients with hormone-resistant PCa resistant to treatment with docetaxel (NCT01260688). The primary end point of the study is PFS. 10.3

11.

c-Met

Met is a tyrosine kinase expressed by osteoblasts and osteoclasts. A transmembrane protein and its only known ligand are HGF and its receptor. Abnormal MET activation in cancer correlates with poor prognosis, where constitutively active MET promotes tumor growth and angiogenesis [86]. It has been demonstrated that the c-Met-mediated signaling pathway is important in PCa progression including local invasion, bone metastasis and castration resistance [86]. c-Met expression is significantly unregulated in the majority of PCa cell lines



with highest expression in the more invasive cell lines, and in vitro models c-Met contributes both to proliferation and invasion. Additionally, in PCa cell lines, c-Met expression is inversely correlated with AR expression and PSA production, with less differentiated cell lines expressing higher levels of c-Met [87]. Cabozantinib (cMet, VEGFR2) Cabozantinib, is an oral multiple TKI that targets c-Met and VEGFR2. MET over expression has been described in PCa particularly in castrate-resistant bone disease [88]. In a xenograft model of mCRPC in bone, cabozantinib blocks the progression of osteolytic and osteoblastic lesions [89]. A Phase II randomized discontinuation trial compared response rate at 12 weeks and PFS after random assignment of cabozantinib versus placebo in patients with mCRPC. The study involved 171 patients, with the primary end points of objective response at 12 weeks and PFS. Treatment with cabozantinib resulted in overall response rate of 68%. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvements on bone scan, including complete resolution in 12%. (The finding of complete resolution on bone scan is of particular interest because that is not commonly seen in PCa. Also, changes in serum markers of bone metastasis appear to corroborate the radiographic findings.) The median PFS was 23.9 weeks in the treatment arm and 5. 9 weeks in the placebo group. Toxicities included fatigue, hypertension and palmar-planter erythrodysesthesia syndrome similar to other TKIs [90]. Based on these findings, several studies are further evaluating cabozantinib in PCa. An ongoing Phase I study of fixed, standard dose of docetaxel and prednisone in combination with cabozantinib at three escalating doses (20, 40 and 60 mg) is underway (NCT01683994). The primary end points are to determine the safety profile of cabozantinib in combination with docetaxel and prednisone, and to determine the maximal tolerated dose. On-going Phase III studies of cabozantinib include a randomized, double-blind, controlled study of cabozantinib versus prednisone in mCRPC patients who have received prior docetaxel and abiraterone acetate or enzalutamide (NCT01605227). A second Phase III study is comparing cabozantinib versus mitoxantrone plus prednisone in men with previously treated symptomatic mCRPC is also underway (NCT01522443).

patient populations based on appropriately identified clinical, pathological or molecular characteristics to increase the likelihood of clinical benefit. The use of PSA as a surrogate marker for disease response is not reliable and may not be an appropriate end point for trial designs. The heterogeneity of PCa especially in the advanced disease state may also be the cause for the inconsistent results.


11.1

12.

Potential development issues

Some encouraging results have been achieved by targeting tyrosine kinases in preclinical models; however, these results do not translate into clinical benefit in large randomized trials in advanced PCa. At this point, it is unclear exactly why some patients respond to TKIs and some do not. In most studies, TKI therapy only works in a subset of patients, which makes designing a study challenging. Future trials should enrich

13.

Conclusion

Despite strong biological rationale for the use of TKIs for the treatment of PCa, the therapeutic effects achieved in clinical trials have been modest thus far. Although there is optimism surrounding c-Met inhibition in two on-going Phase III trials, it is clear that therapeutic development of TKIs needs to evolve to keep up with our understanding of the disease and current treatment strategies. Selective targeting of identified PCa resistance mechanisms may be one approach that maximizes the clinical benefit for patients who may experience progression while on AR-directed therapy. In addition, TKIs may immunologically impact the tumor/tumor microenvironment in a manner that complements emerging immune stimulating therapies such as therapeutic cancer vaccines and immune checkpoint inhibitors. Future trials will require innovative design and appropriate patient selection in order for TKIs to have the opportunity to reach their full potential in the treatment of PCa. 14.

Expert opinion

The use of TKIs has been effective in some malignancies; however, the clinical role of TKIs in PCa still remains elusive. Studies have suggested promise in preclinical models; however, late stage clinical trials have often illuminated clinical shortcomings. One reason for this could be poor clinical trial design. Early PSA changes may not be an optimal surrogate end point or off-study requirement when screening for efficacy of targeted agents. This is highlighted by both sorafenib and cediranib which seem to artificially elevate serum levels of PSA, which may belie underlying stable or responsive disease [84,85]. In these settings, a potential effective therapy may have been discontinued prematurely limiting clinical benefit. More updated PCa trial guidelines now stress the use of radiographic and note PSA parameters to judge treatment efficacy [91]. This past experience with inform future trial design but may also necessitate a review of older studies where end points were PSA driven. Another challenge in clinical trial design is the heterogeneity of PCa, especially in its castrate-resistant state. This could explain why some TKIs only produce responses in a subset of patients. Emerging data suggest that within the mCRPC population of patients there are significant variations in the lethal driver mutations [92]. Furthermore, mutations seemed to be amplified in the late stages of PCa, a common setting for clinical trials. Perhaps, mutational analysis from biopsies can


7



identify which TKIs are likely to have the greatest impact in a given patient. This precision medicine strategy may maximize the likelihood of benefit for TKIs that may only impact 10 -- 20% of patients in a clinical trial that enrolls all patients with mCRPC. Certainly, this approach has limitations in logistics and costs as well as how to prioritize treatments if multiple mutations are present, but it would help gain a better understanding of how effective selected TKI therapy could be in appropriate patients. Therefore, future clinical trials that utilize TKIs should emphasize the need for biopsies to analyze tumors and their molecular driver mutations. Through analysis of response based on mutational read outs, future late stage clinical trials could enroll patients who are likely to respond to such therapies (due to a given mutation) and then determine the potential clinical benefit of the treatment, albeit in a selected subset of patients. One other important point for consideration is that the therapeutic landscape in mCRPC has significantly evolved because many of the TKIs were evaluated in PCa. Many of the previous TKIs were evaluated in patients who had previously been treated with docetaxel or when used in combination with docetaxel. As modern treatment strategies evolved, more effective AR-directed therapy (such as enzalutamide and abiraterone) are being utilized in mCRPC. Although these treatments are beneficial, the patients on these therapies develop resistance through AR-variants or other biochemical pathways that may circumvent normal AR signaling [93,94]. A better understanding of these resistance pathways may allow for appropriate and timely therapeutic deployment of TKIs to possibly suppress these tumor-escape mechanisms. Future studies will have to determine if TKIs used in this manner can salvage the clinical benefit anti-androgen therapy through either sequential or combination strategies. This can be accomplished by better understanding how TKIs are able to impact AR splice variants that are likely present at the initiation of therapy [95]. Again analysis of biopsies to determine the qualitative and quantitative evaluation of AR variants may further highlight populations of potential responders/

8

non-responders, allowing for more appropriate clinical trial design and ultimately clinical utility of appropriate TKIs. In addition, immunotherapy has now demonstrated clinical benefit in mCRPC with the approval of sipuleucel-t, and several other therapies (therapeutic cancer vaccines and immune checkpoint inhibitors) in the last stages of clinical development. Preclinical studies have suggested that TKIs may enhance the immune response through selective depletion of immune regulatory cells or induction of immunologic cell death, both of which potentially enhance the immune response and the ensuing clinical benefit [96,97]. The potential role of TKIs are immunologic adjuvants or companion therapies is only now beginning to be evaluated in clinical studies. Collection of peripheral blood mononuclear cells and serum from patients treated with TKIs could allow a better understanding of their immunologic impact. Ultimately, combination trials may also be more feasible when molecular or immunologic data is available from TKIs evaluated in clinical trials. For example, if multiple TKIs have some benefit in patients who harbor similar mutation profiles, then perhaps such agents could proof synergistic when combined together. Similarly, agents that have a similar impact on the immune system could be combined together or with immunotherapy in future trials with the goal of maximizing the therapeutic potential of agents in such a combination. Also, the development of newer, multi-targeting agents, such as cabozantonib which targets c-Met and VGFR-2, may enhance outcomes by hitting multiple, relevant molecular targets in the PCa proliferation process.

Declaration of interest The authors received National Cancer Institute intramural funding. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.



Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.


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Affiliation Michelle A Ojemuyiwa1, Ravi A Madan2 & William L Dahut†3 † Author for correspondence 1 Clinical Fellow, National Cancer Institute, Medical Oncology Branch, 9000 Rockville Pike Bldg 10, Rm 12N226, Bethesda, MD 20892, USA 2 Associate Investigator, National Cancer Institute, Medical Oncology Branch, 9000 Rockville Pike Bldg 10, Bethesda, MD 20892, USA 3 National Cancer Institute, Medical Oncology Branch, 9000 Rockville Pike, Bethesda, MD 20892, USA E-mail: [email protected]

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