Cancer Investigation, Early Online:1–10, 2015 ISSN: 0735-7907 print / 1532-4192 online C 2015 Informa Healthcare USA, Inc. Copyright  DOI: 10.3109/07357907.2015.1033105

ORIGINAL ARTICLE

Targeted Therapies for Prostate Cancer Roberto Petrioli,1 Edoardo Francini,2 Anna Ida Fiaschi,3 Letizia Laera,1 and Giandomenico Roviello1

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Medical Oncology Unit, University of Siena, Siena, Italy1 Medical Oncology Unit, Policlinico Umberto I Hospital, University of Rome, Roma, Italy2 Pharmacology Unit, University of Siena, Siena, Italy3 drivers of the disease are currently being investigated as single agents or in combination. This review will provide a perspective overview of selected agents that are currently in development, under consideration, or being tested as more effective and targeted treatments of mCRPC.

New therapies for prostate cancer have emerged over the past three years. Nevertheless, none of these agents is curative, and unfortunately, patients often ultimately develop resistance to these agents. Therefore, the development of innovative and effective therapies that overcome these resistances is necessary. Unfortunately, the results of a phase III trial evaluating docetaxel in combination with targeted therapies demonstrated no difference in survival. Moreover, scarce data on the combination of a targeted therapy with new agents are currently available. New trials are investigating these possible combination treatments; the results of these (on-going) clinical studies are awaited.

ANTI-ANGIOGENIC AGENTS Angiogenesis is an important process for the growth, progression, and metastasis of solid tumors. The overexpression of the vascular endothelial growth factor (VEGF) family of proteins is associated with poor prognosis in many cancers, including prostate cancer. VEGF plays a pivotal role in angiogenesis and neovascularization. The plasma VEGF levels have been shown to correlate with metastatic disease progression (11, 12), and both plasma and urine VEGF levels are independent predictors of survival in patients with metastatic disease (13, 14). In addition, preclinical data demonstrated that VEGF inhibition may also prevent further growth of the prostate cancer cell line DU 145 implanted in nude mice (15). Therefore, the inhibition of VEGF is an area of prostate cancer research that has received considerable attention.

Keywords: Prostate cancer, Biologic agents, Target therapy, Docetaxel

INTRODUCTION Prostate cancer, the most common male cancer, accounts for >70,000 deaths in Europe each year (1). Advanced and metastatic prostate adenocarcinoma have traditionally been managed with androgen-deprivation therapy (ADT) (2). However, ADT does not affect adrenal or intra-tumoral androgen production, which may be clinically relevant in disease recurrence. Unfortunately, the treatment of advanced stage prostate cancer nearly always fails, with recurrent castration-resistant tumors typically developing after 18–24 months. After ADT, docetaxel has been considered as the standard of care for the first line of treatment of metastatic castration-resistant prostate cancer (mCRPC) because it confers a survival benefit (3). Over the past decade, several new therapeutic agents have been shown to confer a survival benefit to men with mCRPC, including abiraterone, enzalutamide, radium-223, Sipuleucel-T, and cabazitaxel (Table 1) (4–10). However, none of these agents is curative, and patients unfortunately often ultimately develop resistance to these agents. Therefore, the development of innovative and effective therapies that overcome these resistances is necessary, and antitumor agents that target the molecular

Aflibercept Aflibercept (VEGF Trap) is a recombinant humanized fusion protein comprising the VEGF extracellular domains and the Fc portion of human immunoglobulin IgG1. Aflibercept “traps” VEGF, which prevents the binding of VEGF to its receptor and thus inhibits angiogenesis. Aflibercept has been assessed in preclinical models alone and in conjunction with chemotherapy, including docetaxel, and has shown activity against the DU 145 prostatic carcinoma in immunecompromised mice (16). Furthermore, aflibercept has been assessed in phase I and II clinical trials with docetaxel (17, 18). Subsequently, a randomized, double-blind, phase III, international VENICE trial was designed to evaluate the primary endpoint of overall survival (OS) in chemotherapy-

Correspondence to: Giandomenico Roviello, MD, Medical Oncology Unit, University of Siena, Policlinico Le Scotte, Viale Bracci 11, 53100 Siena, Italy. E-mail: [email protected] Received 28 April 2014; accepted 19 March 2015.

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Table 1. New Therapeutic Agents that Have Shown a Survival Benefit Drug

Mechanism of Action

Study Name

Cabazitaxel Abiraterone Abiraterone Enzalutamide Enzalutamide Radium-223

Chemotherapy Androgen blockade Androgen blockade Androgen blockade Androgen blockade Bone-targeted therapy

TROPIC COU-AA-301 COU-AA-302 AFFIRM PREVAIL ALSYMPCA

Sipuleucel-T

Immunotherapy

IMPACT

na¨ıve men with mCRPC (n = 1,224) treated with a regimen of either placebo or aflibercept, an anti-angiogenic agent, in combination with docetaxel/prednisone (NCT00519285) (19). In April 2012, the trial results indicated that treatment with the investigational regimen did not demonstrate a survival advantage over treatment with docetaxel/prednisone (Table 2) (19). The median overall survival was 22.1 months (95% Confidence Interval (CI): 20·3–24.1) in the aflibercept group and 21.2 months (19.6–23.8) in the placebo group (stratified hazard ratio (HR): 0.94, 95% CI 0·82–1.08; p = .38). In addition, the secondary time-to-event endpoints, including the time to first skeletal-related event and progression-free survival, did not significantly differ between the study groups. However, we detected more tumor responses in patients treated with aflibercept than in those given placebo, and the prostate-specific antigen (PSA) response was greater in the aflibercept group than in the placebo group, although this difference was not statistically significant. However, aflibercept was more toxic than the placebo. The authors reported a higher incidence of grade 3–4 gastrointestinal disorders, haemorrhagic events, hypertension, fatigue, infections and treatment-related fatal adverse events in the aflibercept group than in the placebo group. Bevacizumab Bevacizumab is a humanized monoclonal antibody that inhibits angiogenesis by neutralize circulating VEGF. Bevacizumab is currently approved for the treatment of colon, lung, breast, ovarian and clear cell renal carcinoma in a metastatic setting (20). Bevacizumab has been also investigated in prostate cancer. Although bevacizumab did not elicit a PSA response when used in monotherapy, a previous study of the Cancer and Leukemia Group B reported interesting results for the combination of bevacizumab with docetaxel and estramustine as first line of treatment (21). In this study of 77 patients, a 50% or greater post-therapy decline in PSA was observed in 75% of the patients, and a complete or partial regression of measurable disease was achieved in 59% of the patients (21). The observed median progression-free survival (PFS) time and median overall survival time were 8 months and 24 months, respectively. Patients with CRPC who had previously progressed on docetaxel also reportedly responded to bevacizumab plus docetaxel (22). Based on these findings, a phase III trial of docetaxel and prednisone with and without bevacizumab

Setting Docetaxel pretreated Docetaxel pretreated Chemona¨ıve disease Docetaxel pretreated Chemona¨ıve disease Docetaxel-ineligible or post-docetaxel symptomatic bone metastases without visceral metastases Chemona¨ıve disease Minimally symptomatic disease

(CALGB/ECOG-90401) was launched. The trial evaluated the combination of bevacizumab with docetaxel/prednisone relative to docetaxel/prednisone alone in men with mCRPC (n = 1,050) (23). In spite of an improvement in PFS (median PFS 9.9 months vs. 7.5 months; HR: 0.77, 95% CI: 0.68–0.88; p = .0001) and post-therapy PSA decline (69.5% vs. 57.9%; p = .0002), the median overall survival for patients given docetaxel and bevacizumab was 22.6 months compared with 21.5 months for patients treated with docetaxel (HR: 0.91; 95% CI: 0.78–1.05; stratified log-rank p = .181) (Table 2) (23). Furthermore, the regimen that included bevacizumab was associated with greater morbidity and mortality than the bevacizumab-free regimen (23). Thalidomide/Lenalidomide Thalidomide is an oral angiogenesis inhibitor. In a randomized phase II study of docetaxel plus thalidomide or placebo in patients with mCRPC, 50% more patients showed a PSA response (53% vs. 37%; p = .32), and the median overall survival was extended (29 vs. 15 months, p = .11) in the thalidomide arm. Although acceptable safety was reported, thromboembolic events occurred in 28% of the patients who did not receive prophylactic anticoagulation (24). Lenalidomide is a thalidomide derivative with immunomodulatory and anti-angiogenic properties. In a phase I study in CRPC (n = 31), lenalidomide plus docetaxel showed similar 50% PSA response rates in chemotherapy-naive and previously treated patients (47% vs. 50%) (25). Therefore, a phase III study of docetaxel with or without lenalidomide in men with mCRCP (n = 1,059) (NCT00988208) was launched. Unfortunately, this trial was terminated early based on interim findings, which showed that the addition of lenalidomide to a regimen of docetaxel/prednisone did not confer additional survival benefit to mCRPC patients (Table 2) (26). In addition, bevacizumab was paired with thalidomide and docetaxel/prednisone in a phase II trial to treat advanced prostate cancer (27). This regimen elicited high 50% PSA response rates (88%). However, this combination did not improve the treatment efficacy relative to docetaxel-based chemotherapy. TYROSINE KINASE INHIBITOR (TKI) Dasatinib Dasatinib is a potent inhibitor of the sarcoma (Src) family non-receptor tyrosine kinases, which are mediators of intracellular signaling pathways that control cell growth, Cancer Investigation

Targeted Therapies for Prostate Cancer  Table 2. Selected Ongoing and Concluded Phase III Trials with Targeted Therapy in Prostate Cancer Drug

Experimental vs. Control Arm

NCT00110214

OS

NCT00988208

OS

NCT00744497

Pain response

NCT01522443

Completed; no difference in OS. Terminated early; no difference in OS. Completed; no difference in OS. Ongoing.

OS

NCT01605227

Ongoing.

OS

NCT00676650

OS, PFS

NCT00134056

Zibotentan+docetaxel vs. placebo+docetaxel

OS

NCT00617669

Completed; no difference in OS. Terminated early; no difference in OS. Completed; no difference in OS.

Ipilimumab vs. placebo Ipilimumab vs. placebo

OS OS

NCT01057810 NCT00861614

Immunotherapy Clusterin inhibitor

Tasquinimod vs. placebo Custirsen+docetaxel+prednisone vs. placebo+docetaxel+prednisone

OS OS

NCT01234311 NCT01188187

Clusterin inhibitor

Custirsen+docetaxel retreatment or cabazitaxel+prednisone vs. placebo+ docetaxel retreatment or cabazitaxel+prednisone

Pain response

NCT01083615

Bevacizumab

Angiogenesis inhibitor Angiogenesis inhibitor

Bevacizumab+docetaxel+prednisone vs. placebo+docetaxel+prednisone Lenolidamide+docetaxel+prednisone vs. placebo+docetaxel+prednisone Dasatinib+docetaxel+prednisone vs. placebo+docetaxel+prednisone Cabozantinib vs. mitoxantrone+ prednisone Cabozantinib vs. placebo

Ipilimumab Ipilimumab

Tyrosine kinase inhibitor Tyrosine kinase inhibitor Tyrosine kinase inhibitor Tyrosine kinase inhibitor Endothelin receptor antagonists Endothelin receptor antagonists Immunotherapy Immunotherapy

Tasquinimod Custirsen (OGX-011) Custirsen (OGX-011)

Cabozantinib Sunitinib Atrasentan

Zibotentan

Status/Outcome Completed; no difference in OS.

Aflibercept+docetaxel+prednisone vs. placebo+docetaxel+prednisone

Cabozantinib

Clinical Trial Identifier NCT00519285

Angiogenesis inhibitor

Dasatinib

Primary Endpoint Overall survival (OS) OS

Aflibercept

Lenolidamide

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Target

Sunitinib+prednisone vs. placebo+prednisone Atrasentan+docetaxel+prednisone vs. placebo+docetaxel+prednisone

migration and invasion. Src signaling plays an important role in normal bone turnover and is essential for normal osteoclast functioning and osteoblast proliferation. It has also been implicated in the promotion of bone metastasis in prostate cancer (28). The potential of Src inhibition in cancer treatment was confirmed in preclinical studies of dasatinib that showed reduced proliferation and migration of prostate cancer cells (including hormone-refractory cells) (29, 30) and reductions in lymph node metastases in mice (29). Dasatinib has also demonstrated pro-bone effects by inhibiting bone resorption and bone metastases (31, 32), which are the processes that are critical mCRPC because bone metastases are prevalent in this malignancy. In a phase II trial of patients with mCRCP, treatment with dasatinib reduced the PSA concentration, elicited tumor and decreased the levels of the bone turnover markers urinary N-telopeptide (uNTx) and bone-specific alkaline phosphatase (BAP) (33). Furthermore, the results of a phase I/II trial showed that the combination of dasatinib and docetaxel in patients with mCRCP was safe and well tolerated (34). Based on the positive results from this phase I/II study, a randomized phase III study that compared docetaxel with dasatinib to docetaxel with placebo in castration-resistant prostate cancer was conducted (35). A total of 1,522 eligible patients were randomly assigned to different treatment groups. The median overall survival was C 2015 Informa Healthcare USA, Inc. Copyright 

Ongoing. Interim analysis: no difference in OS. Ongoing. Completed, no study results posted. Completed, no study results posted.

21.5 months (95% CI: 20.3–22.8) in the dasatinib group and 21.2 months (20.0–23.4 months) in the placebo group (stratified HR: 0.99, 95% CI: 0.87–1.13; p = .90) (Table 2). Among the secondary endpoints, the median PFS and median time to PSA progression were similar between placebo and dasatinib groups, as were the other secondary endpoints of the study. The most common grade 3–4 adverse events included diarrhea, fatigue and asthenia. Therefore, the addition of dasatinib to docetaxel did not improve the overall survival for chemotherapy-naive men with mCRPC. To date, an on-going study (NCT01254864) is exploring the hypothesis that further suppressing of androgens via CYP17 inhibition with abiraterone might improve the efficacy of dasatinib in patients with mCRCP.

Cabozantinib Cabozantinib is a dual-action inhibitor of the Met receptor tyrosine kinase and the VEGF receptor 2 (VEGFR2). Met signaling promotes tumor invasion, growth and metastasis, and Met and VEGFR2 are thought to act synergistically in angiogenesis (36). In a phase II study of men with mCRPC, treatment with cabozantinib improved the PFS, reduced soft tissue lesions, reduced bone lesions on scans and decreased pain compared with placebo (37). Objective tumor

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shrinkage occurred in 84% of the patients. Of the patients with bone metastases, 86% showed complete or partial resolution of bone lesions and 64% reported less pain. In a retrospective analysis, a ≥30% reduction in bone scan lesion area, CTC conversion (>5 to ≤4/7.5 mL of blood) and improved pain intensity after six weeks of treatment with cabozantinib was associated with an overall survival benefit (38). Two phase-III trials of cabozantinib as the third line of treatment are ongoing but are not recruiting male participants with mCRPC, with prior docetaxel and prior abiraterone or enzalutamide (COMET-1 and COMET-2, respectively) (Table 2). However, the latest results from the COMET-1 trial show that cabozantinib did not improve survival compared with prednisone in men with mCRPC whose disease had progressed after treatment with docetaxel as well as abiraterone and/or enzalutamide. Overall survival was the primary outcome in COMET-1, and it was not significantly different between the cabozantinib and prednisone groups (median, 11 months vs. 9.8 months; HR: 0.9; 95% CI, 0.76–1.06; p = .212). However, PFS was significantly better, with a median of 5.5 months with cabozantinib versus 2.8 months with prednisone (HR: 0.50; 95% CI: 0.42–0.60; p < .0001). Sunitinib Sunitinib is a multi-targeted TKI of PDGFR, VEGFR and KIT. Three phase-II trials of single agent sunitinib for the treatment of progressive mCRCP suggested antitumor activity with an acceptable safety profile (39,40). Based on these promising results, a phase III trial of sunitinib and prednisone in men with progressive mCRPC after docetaxel-based chemotherapy was conducted. However, the addition of sunitinib to prednisone did not improve the overall survival compared with placebo for patients suffering from docetaxel-refractory mCRPC (Table 2) (41). In addition, sunitinib treatment showed significant toxicity (rate of discontinuation because of adverse events 27% vs. 7% for placebo). Other Tyrosine Kinase Inhibitors Sorafenib, Erlotinib, Gefitinib and Vandatinib have been clinically evaluated alone or in combination with docetaxelbased chemotherapy in men with mCRPC. However, neither of these drugs yielded an additional benefit alone or in combination relative to a docetaxel/corticosteroid regimen (42). Lastly, Saracatinib (AZD0530) is an oral non-receptor TKI that targets Src kinases and has been shown to have activity in orthotopic animal models of CRPC (43). Two phase-II studies of Saracatinib in CRPC in chemotherapy-naive and post-docetaxel settings are underway. ENDOTHELIN RECEPTOR ANTAGONISTS Endothelins are small proteins implicated in tumor growth and metastasis (44), and the inhibition of pathways that involve endothelins has garnered interest in cancer research as potential treatments for both primary tumors and bone metastases. Two agents (atrasentan and zibotentan) have been developed for patients with mCRCP.

Atrasentan Atrasentan is an orally bioavailable small molecule inhibitor of endothelin receptor subtype A (ETA ). This interaction inhibited the development and progression of metastases in preclinical models (45). A phase I/II study of atrasentan with docetaxel and prednisone in men with mCRCP appeared safe at full doses of atrasentan and docetaxel with reasonable activity based on PSA and RECIST criteria (46). Therefore, a phase III study of atrasentan/docetaxel/ prednisone compared with docetaxel/prednisone in patients with CRPC and bone metastases (SWOG-S0421 trial) (47) involved 991 eligible patients. The authors reported no differences in the overall survival (median overall survival 18 months vs. 17 months, respectively; HR: 1.01, 95% CI: 0.87–1.18; p = .88) (Table 2), and the differences in the secondary endpoints, such as PFS and PSA response, were similarly unremarkable (47). In addition, the toxicities were reportedly similar between the two arms (47). Zibotentan Zibotentan is an oral-specific ETA receptor antagonist that showed potential efficacy in prolonging overall survival compared with placebo in a phase II, placebo-controlled study of individuals with mCRPC (48). The finding of this study led to the launch of three phase-III studies of chemotherapyna¨ıve patients (48–51), including the ENTHUSE M1C trial, which compared a regimen of docetaxel in combination with zibotentan with docetaxel/placebo in patients with mCRPC (NCT00617669) (52). A total of 1,052 patients received the study treatment (docetaxel–zibotentan, n = 524; docetaxel–placebo, n = 528). The overall survival did not differ between patients receiving docetaxel–zibotentan and those receiving docetaxel–placebo (HR: 1.00; 95% CI: 0.84–1.18; p = .963 (Table 2) with median overall survival of 20.0 and 19.2 months, respectively). The secondary endpoints, including time to pain progression (median 9.3 vs. 10.0 months, respectively) or pain response (odds ratio: 0.84; 95% CI: 0.61–1.16; p = .283), also did not differ significantly. The most commonly reported adverse event was peripheral edema in more than 50% of patients treated with zibotentan. The other two placebo-controlled studies of zibotentan monotherapy (in either metastatic or non-metastatic patients) were terminated due to lack of efficacy. IMMUNOTHERAPIES The regulatory approval of sipuleucel-T for mCRPC has validated the modulation of the immune system as an effective strategy in the treatment of prostate cancer. In this setting, two biological agents (impilimumab and tasquinimod) have been developed for men with prostate cancer. Ipilimumab Ipilimumab is a human monoclonal antibody against cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). CTLA-4 plays a key role in regulating natural immune responses; the down-regulation of CTLA-4 increases the immune response (53). Objective and PSA responses have been described in Cancer Investigation

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phase II studies of ipilimumab in prostate cancer (54, 55). The use of radiotherapy was based on preclinical data that suggested that radiation enhances immune response by upregulating the expression of tumor antigens (56). Recently, two phase-III trials of ipilimumab in chemotherapy-naive and post-docetaxel mCRPC settings have completed accrual (Table 2). The results of the phase III trial in a post-docetaxel mCRPC setting were recently reported. Men were randomized to receive bone-directed radiotherapy before either ipilimumab (n = 399) or placebo (n = 400) (57). Based on the intention to treat analysis (n = 799), ipilimumab did not significantly improve the median overall survival compared with placebo (11.2 vs. 10 months; HR: 0.85; 95% CI: 0.72–1.00; p = .053). Immune-related treatment-related adverse effects (AEs) were common in the ipilimumab group (58). Tasquinimod Tasquinimod is a quinoline-3-carboxamide analogue that possesses anti-angiogenic and immunomodulatory properties (upregulates thrombospondin and targets S100A9 [MRP14], which is expressed on myeloid-derived suppressor cells) (59). In a randomized placebo-controlled, phase II trial of chemo-naive patients, tasquinimod demonstrated improvement in the median PFS (7.6 vs. 3.3 months) (60). A phase III, placebo-controlled, randomized trial in chemo-naive mCRPC patients of tasquinimod has recently completed accrual with the primary endpoint of PFS (Table 2). In addition, a phase II placebo-controlled trial is evaluating tasquinimod as a maintenance therapy in docetaxel-responding patients. T-cell Receptor and Chimeric Antigen Receptor Transgenes Tumor-specific T cells can be isolated from some tumors, and T cells can be activated ex vivo to respond against cancer cells (61). These genetic modifications of T cells using genes encoding antigen receptors are used to generate tumor-reactive T cells in a process termed as genetic redirection of specificity. The chimeric antigen receptor (CAR) is a type of antigen receptor used in genetic redirection (62). Genes encoding this receptor are inserted into patient’s T cells using viral vectors to generate tumor-reactive T cells. Prostate cancer may also be responsive to CAR T cells with a report of two partial responses from five patients in a clinical study using CAR T cells redirected toward prostate surface membrane antigen (PSMA) (63).

suggesting the potential clinical application of custirsen in the treatment of docetaxel-refractory patients (66). In a randomized phase II trial, weekly intravenous (i.v.) custirsen plus docetaxel extended median survival compared with docetaxel alone (23.8 vs. 16.9 months) (67). Another phase II trial demonstrated the efficacy and feasibility of the combination of custirsen and either docetaxel/prednisone or mitoxantrone/prednisone in patients with progressive mCRPC following first line of docetaxel therapy (68). Based on these promising data, three phase-III trials that combine OGX-011 with a chemotherapeutic (docetaxel and cabazitaxel) agents are ongoing in mCRPC (Table 2). A regimen of custirsen with docetaxel/prednisone is presently being investigated in a randomized, open label, international SYNERGY trial in patients with mCRPC (n = 1,000) (Table 2). The preliminary results showed a PSA decrease by >50% in 58% of the patients in the custirsen arm and 54% in the control arm (67). The median PFS favored the custirsen arm at 7.3 months (95% CI: 5.3–8.8) relative to the control arm at 6.1 months (95% CI: 3.7–8.6) (67). Treatment with custirsen and docetaxel/prednisone was well tolerated. Rigors and fever were reported as common adverse events (67). Another randomized, placebo-controlled, double-blind phase III trial is currently evaluating custirsen pain palliation relative to placebo in patients with mCRPC receiving docetaxel retreatment or cabazitaxel as a second line of therapy (NCT01083615). Other Clusterin Inhibitors HSP-90 is another multifaceted molecular chaperone implicated in the progression of prostate cancer by the induction of several upstream signaling pathways that promote aberrant androgen receptor activation and stabilize the androgen receptor protein. Ganetespib is a novel small molecule inhibitor of Hsp90 that was tested in a phase II trial (69) and did not improve the PFS. Heat shock protein 27 (Hsp27) chaperones the androgen receptor, which enhances the transactivation of androgen receptor-regulated genes. OGX-427 is a second-generation antisense agent that inhibits Hsp27 expression (70) and was tested in a randomized phase II trial of chemo-naive patients with minimal or no symptoms. The addition, OGX-427 is expected to restore sensitivity to antisense agent and improve survival outcomes.

OTHER PATHWAYS CLUSTERIN INHIBITOR Clusterin is a cytoprotective chaperone whose transcription is promoted by the androgen receptor and heat shock Factor-1, a key mediator of carcinogenesis (64). Clusterin represents a novel target in prostate cancer, as preclinical data have demonstrated that overexpression of clusterin results in androgen-independent growth (65). Custirsen (OGX-011) Custirsen (OGX-011), an antisense inhibitor of clusterin that suppresses clusterin expression, was found to re-sensitize docetaxel-refractory PC3 prostate cancer cells to docetaxel, C 2015 Informa Healthcare USA, Inc. Copyright 

B-cell Lymphoma 2 (Bcl-2) B-cell lymphoma 2 is the founding member of the Bcl-2 family of regulator proteins that regulate apoptosis. Bcl-2 is considered an important anti-apoptotic protein and is thus classified as an oncogene. Bcl-2 is overexpressed in a significant number of men with CRPC. The inhibition of Bcl-2 expression increases apoptosis and decreases proliferation and angiogenesis (71). Oblimersen (Genasense, G3139) is an inhibitor of Bcl2 protein expression (71) tested in a multi-center, phase II study of men with chemotherapy-naıve mCRPC with PSA progression (72).

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AT-101 (R-gossypol acetic acid) is a small molecule oral inhibitor of the Bcl-2 family. In 2011, a randomized phase II trial by Sonpavde et al. (73) compared the addition of AT-10 with docetaxel-based chemotherapy. The overall survival and secondary endpoints did not significantly differ between the two groups. Insulin-Like Growth Factor (IGF) Pathway The insulin-like growth factor pathway, which includes IGF receptor-1 (IGF-1R) and its ligands, IGF-I and IGF-II, plays a major role in the proliferation of cancer cells, including prostate cancer cells (74). Animal models indicated that the blockade of IGF-IR in combination with chemotherapy leads to chemosensitization, which improved the antitumor activity of docetaxel (74). Figitumumab and cixutumumab are fully human monoclonal antibodies that target IGF-1R. The former was tested in a phase II study in combination with docetaxel (NCT00313781) and in a single arm, open label study of chemotherapy-naive mCRPC (NCT00520481). The latter was tested in a phase II study either as monotherapy or in combination with temsirolimus (NCT01026623). PI3K/Akt/mTOR Pathway The mammalian target of rapamycin (mTOR) is a serinethreonine kinase that regulates cell growth and cell cycle progression and integrates signals from growth factors. The mTOR pathway may be aberrantly activated due to increased IGFR and EGFR signaling, which activate the mutations or amplification of kinase genes, or due to a loss of function of phosphate and tensin homolog (PTEN). The lipid and protein phosphatase, PTEN, is a key negative regulator of Akt activity. The aberrant expression of PI3K and AKT1 genes or loss of PTEN tumor suppression gene leads to the downstream upregulation of mTOR and tumorigenesis. Therefore, multiple phase II studies of mTOR inhibitors as a single agent or in combination with chemotherapeutics or anti-androgen agents are ongoing. The rationale behind these trials is that mTOR inhibitor in a combination therapy is expected to restore sensitivity to prior treatment or overcome resistance to prior first line of therapy. Radiolabeled Monoclonal Antibody Prostate surface membrane antigen is a type II membrane glycoprotein whose expression is markedly upregulated in prostate cancer (75), monoclonal antibodies that target PSMA are in the advanced phases of development. To date, radio-immunoconjugates of J591 and radiopharmaceuticals (Y-90 and Lu-177) have demonstrated more promising activity (76–78). Several phase II trials are currently evaluating these new drugs in chemo-naive mCRCP patients. DISCUSSION Targeted-therapies, which specifically inhibit growth factor receptors and their related signaling pathways, are promising innovative medical oncology treatment approaches. The advantage of such novel combination therapies is their

increased tumor cell specificity and efficacy combined with acceptable toxicity and side effects. Prostate cancer is fuelled by androgen axis and progresses even after androgen deprivation. Several mechanisms have been identified to explain persistent androgen signaling in CRPC (2, 79), including increased androgen receptor gene expression, the mutation of the androgen receptor gene or upregulation of enzymes involved in androgen synthesis (79–81). Furthermore, other pathways of carcinogenesis may be invoked to aid ligand-independent aberrant androgen receptor signaling in progression of prostate cancer (82). These data establish the critical role of androgen receptor signaling and provide the rationale for targeting the androgen synthesis pathway. In this setting, several new therapeutic agents (abiraterone, enzalutamide, radium-223, cabazitaxel and sipleucel-T) (4–10) impair androgen receptor signaling, and phase III trials showed that they provided a survival benefit for men with mCRPC (Table 1). Nevertheless, none of these agents is curative, and patients unfortunately often develop resistance to these agents. As matter of fact, a complex series of molecular events, such as oncogene activation, tumor suppressor gene inactivation, apoptosis evasion, intratumoral androgen production, and aberrant androgen receptor activation, lead to the development of resistance to new agents for mCRCP. Furthermore, androgen receptor signaling may cooperate with other oncogenic pathways associated with epithelial mesenchymal transition, anoikis and cell survival to promote progression to mCRPC (83). In addition, several studies have suggested mechanisms of intrinsic or acquired resistance between new anti-androgens therapies (abiraterone and enzalutamide) (84, 85). Moreover, very little data are available on the efficacy of other treatment options after progression of all new agents (86, 87). However, new drugs and targets as well as information on resistance mechanisms, sequencing and combinations are available. Hypothetically, targeted therapy with one of these novel drugs could restore sensitivity to one of these prior treatments or overcome resistance to a prior line of therapy. Unfortunately, previous studies of target therapy for mCRCP are disappointing, as described herein. In fact, large phase III trials have now assessed docetaxel and prednisone with or without a targeted agent for men with mCRCP and showed no difference in survival between arms and increased toxicity in most experimental groups. Furthermore, some studies were terminated early based on the negative interim findings. Nevertheless, although targeted therapy fails in combination with docetaxel, some data are now available on the combination of a targeted therapy with one of the new agents available in the market. Therefore, new trials are establishing the possible role of targeted therapy in the light of new treatment options. Specifically, the combination of targeted therapy and endocrine therapy has yielded promising results. The Bolero trial (88) for breast cancer patients constitutes an example of this approach. In this study, the mTOR inhibitor everolimus showed antitumor activity in combination with endocrine therapy because resistance to endocrine Cancer Investigation

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Targeted Therapies for Prostate Cancer  therapy is associated with the activation of mTOR intracellular signaling pathway. Based on this hypothesis, many trails are evaluating a combination of target therapy and new prostate cancer agents. For example, a randomized, open label phase II trial of abiraterone and prednisone with or without dasatinib was conducted in mCRPC patients (NCT01685125). NCT01578655 and NCT01083615 are two other phase III trials that are investigating the antisense inhibitor of clusterin Custirsen (OGX-011) with cabazitaxel and prednisone as a second line of chemotherapy for mCRPC. Furthermore, the mTOR inhibitor everolimus was tested with docetaxel and bevacizumab in mCRPC patients in a phase I/II trial (NCT00574769) or with carboplatin and prednisone in mCRPC patients with prior docetaxel progression (NCT01051570). In addition, temsirolimus with cixutumumab (NCT01685125) was investigated in chemotherapynaive CRPC. All of these combination treatments will widen the therapeutic spectrum for prostate cancer; the results of (on-going) clinical trials are eagerly awaited. However, based on the information available from preliminary data of published trails, some drugs could be investigated in specified setting of patients. For example, the latest results from the COMET-1 trial show that cabozantinib did not improve survival compared with prednisone in men with mCRPC heavily pre-treated, nevertheless cabozantinib has demonstrated improvements in bone scans, pain, analgesic use, measurable soft tissue disease and bone biomarkers in chemotherapy-pre-treated mCRCP patients (37). Therefore, although cabozantinib does not seem to be a valid option after new prostate cancer agent’s progression, its use may be indicated in a subset of patients with meaningful bone disease. A similar approach could be applied to dasatinib, which is a potent inhibitor of the Src family that plays an important role in bone turnover. In the future, specific trails could assess the impact of these drugs in combination with new prostate cancer agents on patients with extended bone disease. CONCLUSIONS In this review, we presented recent studies of possible targeted therapies in prostate cancer patients. The majority of trials examined the combination of a target therapy with the standard docetaxel-based regimen in mCRPC patients. Unfortunately, the results of these studies are disappointing. In fact, the results of large phase III trials that evaluated docetaxel in combination with other agents, such as anti-angiogenic agents (bevacizumab, aflibercept and lenalinomide), a Src kinase inhibitor (dasatinib), and endothelin receptor antagonists (atrasentan and zibotentan), showed no difference in survival and instead resulted in increased toxicity in most experimental groups. Therefore, no targeted therapy can currently be recommended in prostate cancer patients. The modest impact of targeted therapy on the survival of mCRCP patients may be due to several reasons, such as a heterogeneous study population, unique interactions between docetaxel and molecularly targeted therapies that result in a consistent bias against the targeted C 2015 Informa Healthcare USA, Inc. Copyright 

agents, paracrine or intracrine androgen signaling that drive resistance to therapy, persistent but low concentrations of androgens that drive disease progression, and multiple and redundant pathways in the very advanced stages of mCRCP. In addition, the small effect of targeted therapy on the overall survival of mCRCP patients underscores the limitations of uncontrolled phase II trials and the challenges involved in translating preclinical observations to a clinical setting. Promising randomized phase II trials have not translated into successful phase III trials. Therefore, more extensive preclinical assessments and initial clinical confirmation are needed before proceeding to phase III trials. Nevertheless, further studies of available options, such as abiraterone, enzalutamide or cabazitaxel, are awaited to definitely assess the role of targeted therapy in mCRCP. If these awaited results are promising, we believe that targeted therapy shall be investigated as an addition to traditional hormonal therapy in high-risk localized prostate cancer patients to improve cure rates and prolong the period from first hormonal manipulation to first line of chemotherapy. DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article. REFERENCES 1. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, Forman D. Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in 2012. Eur J Cancer 2013;49:1374–1403 2. Chen Y, Clegg NJ, Scher HI. Anti-androgens and androgendepleting therapies in prostate cancer: New agents for an established target. Lancet Oncol 2009;10:981–991. 3. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Th´eodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502–1512. 4. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fl´echon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364:1995–2005. 5. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, Fl´echon A, Mainwaring P, Fleming M, Hainsworth JD, Hirmand M, Selby B, Seely L, de Bono JS. AFFIRM investigators increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012, Sep 27;367(13):1187–1197. 6. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Foss˚a SD, Chodacki A, Wiechno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall’Oglio M, Franz´en L, Coleman R, Vogelzang NJ, O’Bryan-Tear CG, Staudacher K, Garcia-Vargas J, Shan M, Bruland ØS, Sartor O; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369:213–223. 7. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G, Bodrogi I, Mackenzie MJ, Shen L, Roessner M, Gupta S, Sartor AO; TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant

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