Prostate and Prostatic Diseases (2011) 14, 206–218 & 2011 Macmillan Publishers Limited All rights reserved 1365-7852/11 www.nature.com/pcan REVIEW

Emerging therapeutic approaches in the management of metastatic castration-resistant

ES Antonarakis1 and AJ Armstrong2,3 1Prostate Cancer Research Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA; 2Department of Medicine, Duke Cancer Institute and the Duke Prostate Center, Duke University, Durham, NC, USA and 3Department of Surgery, Duke Cancer Institute and the Duke Prostate Center, Duke University, Durham, NC, USA

Although treatment options for men with castration-resistant prostate cancer (CRPC) have improved with the recent and anticipated approvals of novel immunotherapeutic, hormonal, chemotherapeutic and bone-targeted agents, clinical benefit with these systemic therapies is transient and survival times remain unacceptably short. Thus, we devote the second section of this two-part review to discussing emerging therapeutic paradigms and research strategies that are entering phase II and III clinical testing for men with metastatic CRPC. We will discuss a range of emerging hormonal, immunomodulatory, antiangiogenic, epigenetic and cell survival pathway inhibitors in current clinical trials, with an emphasis on how these therapies may complement our existing treatment options. Prostate Cancer and Prostatic Diseases (2011) 14, 206–218; doi:10.1038/pcan.2011.24; published online 17 May 2011

Keywords: castrate-resistant prostate cancer; novel therapies; clinical trials; drug development

Introduction pathways (Figure 1). Such cellular processes reflect the basic hallmarks of cancer and include angiogenesis and Although we now have four therapies that have been tumor microenvironment interactions, cell growth and shown to extend survival in patients with metastatic proliferation, apoptosis, cell nutrition, DNA repair and castration-resistant prostate cancer (CRPC) (docetaxel, epigenetic regulation.2 This review is the second article cabazitaxel, sipuleucel-T and ), none in a series of two papers discussing therapeutic strategies of these approaches are curative. To this end, annual for CRPC. Although the first review focused on Food mortality rates from prostate cancer in the United States and Drug Administration approved and available treat- remain unacceptably high at B30 000 deaths per year.1 ment options for these patients, this review will touch For this reason, the discovery of novel treatment upon several novel therapies currently in clinical devel- strategies for this patient population remains a critical opment that may enter the therapeutic arsenal in the next endeavor and the identification of alternative therapeutic 5 years. Such therapies include additional - targets has never been more actively pursued. Because modulating approaches, novel , angio- exploitation of the androgen axis and the antitumor genesis inhibitors, mammalian target of rapamycin immune response has yielded fruit in recent years, (mTOR) pathway inhibitors, apoptosis-inducing drugs, several drug development efforts continue to focus on -like (IGF) pathway antagonists, these avenues. This has resulted in the progression to epigenetic therapies and poly-ADP ribose polymerase phase III development of several novel androgen- (PARP) inhibitors. directed agents (for example, orteronel, MDV3100) and immune-modulating drugs (for example, ). In addition to these strategies, our recently accelerated Novel androgen-directed approaches understanding of other biological and cellular processes for metastatic CRPC driving prostate cancer progression and metastasis has fueled the preclinical and clinical exploration of myriad The first review in this two-part series discussed the oral molecular targets comprising alternative oncogenic agent abiraterone, a drug that suppresses extra-gonadal androgen synthesis by inhibiting CYP17 (C17,20-lyase and 17a-hydroxylase). This review will outline some Correspondence: Dr ES Antonarakis, Prostate Cancer Research additional (AR)-directed therapies Program, Sidney Kimmel Comprehensive Cancer Center at Johns that may hold promise in the near future. Hopkins, 1650 Orleans Street, CRB1-1M45, Baltimore, MD 21231-1000, USA. E-mail: [email protected] Orteronel Received 11 March 2011; revised 11 April 2011; accepted 17 April 2011; Orteronel (TAK-700) is an oral, non-steroidal, selective published online 17 May 2011 CYP17 blocker that is a more potent inhibitor of Emerging approaches for castration-resistant prostate cancer ES Antonarakis and AJ Armstrong 207

Figure 1 Promising pathways and targets in metastatic CRPC. A; androgen; AR, androgen receptor; APC, antigen-presenting cell; CRPC, castration-resistant prostate cancer; CoAct, transcriptional coactivators; DNMT, DNA methyltransferase; ERK, extracellular signal-regulated kinase; GM-CSF, granulocyte–macrophage-colony-stimulating factor; HDAC, histone deacetylase; HSP, heat-shock protein; IGF-1R, insulin- like -1; MEK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PAP, prostatic acid phosphatase; PARP, poly (ADP-ribose) polymerase; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homologue deleted on chromosome ten; VEGF-R, vascular endothelial growth factor receptor.

C17,20-lyase activity than 17a-hydroxylase activity, lead- sone in patients with -naı¨ve metastatic ing to the suppression of extra-gonadal (autocrine, CRPC, whereas the second study (C21005) will investi- paracrine, adrenal) androgen biosynthesis without im- gate the same treatment arms in patients with metastatic pairing cortisol production at the doses studied3 (Figure 1). CRPC that have progressed during or after docetaxel- This has the theoretical advantage of preventing ACTH based chemotherapy (Table 1). Both trials have been feedback upregulation and avoiding complications powered to detect a 20–25% improvement in overall related to secondary mineralocorticoid excess (hyperten- survival between treatment groups. Preliminary results sion, fluid retention, hypokalemia and need for corticos- suggest that orteronel (with or without prednisone) may teroids). Moreover, orteronel is able to inhibit C17,20- emerge as an alternative to abiraterone acetate in the lyase activity at lower nanomolar concentrations than future. Although the theoretical lack of requirement for abiraterone.4 Also, the use of a non-steroidal moiety prednisone is appealing given the recent approval of minimizes the risks of drug metabolism and pharmaco- sipuleucel-T (which is probably most kinetic effects, as well as the formation of steroidal effective without concurrent immunosuppressive ster- metabolites that might have AR agonistic activity. oids), both of the ongoing phase III programs have In a phase I/II study using orteronel in patients with utilized the combination of orteronel with prednisone, metastatic CRPC (one-third of which had previous and future studies of orteronel without prednisone will treatment), 52% of men receiving daily be needed to clarify its single-agent utility in CRPC. doses of X600 mg showed X50% PSA reductions (including 29% of men who showed X90% PSA declines).5 Importantly, the incidence of hypertension MDV3100 and hypokalemia in this trial was low, supporting the A slightly different AR-directed approach has focused on notion of preferential inhibition of C17,20-lyase over 17a- the development of second-generation anti- hydroxylase in human beings. Common toxicities ob- that have advantages over the previous agents in this served with orteronel included fatigue (47%), emesis class (, and ). One such (30%), constipation (21%) and anorexia (12%). Based drug is MDV3100, an oral non-steroidal AR antagonist on the initial promising activity of this agent, a larger with a binding affinity for the AR, which is five times phase II trial of orteronel (without prednisone) in non- greater than that of bicalutamide.6 Importantly, metastatic CRPC and two multicenter randomized phase MDV3100 remains a potent antagonist of the AR in the III trials in metastatic CRPC were launched. castration-resistant state, even in the setting of over- The first phase III study (C21004) will compare expressed or constitutively activated AR.7 In addition, orteronel plus prednisone against placebo plus predni- unlike other anti-androgens that may also function as

Prostate Cancer and Prostatic Diseases Emerging approaches for castration-resistant prostate cancer ES Antonarakis and AJ Armstrong 208 Table 1 Selected ongoing phase II and III clinical trials of novel targeted therapies for men with metastatic CRPC

Target/pathway Agent Phase Treatment arm(s) 1ary end point Identifier

AR-directed approaches CYP17 (androgen Orteronel III Randomized trial: orteronel 400 mg orally twice daily Overall survival NCT01193257 synthesis) vs placebo orally twice daily (post-docetaxel)

III Randomized trial: orteronel 400 mg orally twice daily Overall survival NCT01193244 vs placebo orally twice daily (pre-docetaxel) and progression-free survival (co-primary)

TOK-001 I/II Single-arm trial: TOK-001 650–2600 mg orally daily Phase I: Safety NCT00959959 (dose escalation) (pre-docetaxel) Phase II: X50% PSA k

AR MDV3100 III Randomized trial: MDV3100 160 mg orally daily vs Overall survival NCT00974311 placebo orally daily (post-docetaxel)

III Randomized trial: MDV3100 160 mg orally daily vs Overall survival and NCT01212991 placebo orally daily (pre-docetaxel) progression-free survival (co-primary)

ARN-509 I/II Single-arm trial: ARN-509 30–300 mg orally daily Phase I: Safety NCT01171898 (dose escalation) (pre- and post-docetaxel) Phase II: Time to PSA progression (X25% m)

Immunotherapies CTLA-4 (immune Ipilimumab III Randomized trial: bone irradiation, then ipilimumab Overall survival NCT00861614 checkpoint) 10 mg/kg i.v. every 3 weeks vs placebo i.v. every 3 weeks (post-docetaxel)

III Randomized trial: ipilimumab 10 mg/kg i.v. every Overall survival NCT01057810 3 weeks vs placebo i.v. every 3 weeks (pre-docetaxel)

Other targeted therapies VEGF-R II Single-arm trial: sorafenib 400 mg orally twice daily Time to disease NCT00414388 (angiogenesis) (post-docetaxel) progression

II Single-arm trial: sorafenib 400 mg orally twice daily X50% PSA k NCT00589420 plus docetaxel 75 mg/m2 i.v. every 3 weeks (pre-docetaxel)

Cediranib II Randomized trial: 20 mg orally daily plus Progression-free NCT01260688 100 mg orally daily vs cediranib 20 mg survival orally daily (post-docetaxel)

Ramucirumab II Randomized trial: (see below) Progression-free NCT00683475 6 mg/kg i.v. every 1 week plus mitoxantrone survival 12 mg/m2 i.v. every 3 weeks vs 6 mg/kg i.v. every 1 week plus mitoxantrone 12 mg/m2 i.v. every 3 weeks (post-docetaxel)

VEGF-Trap III Randomized trial: aflibercept 6 mg/kg i.v. Overall survival NCT00519285 (angiogenesis) plus docetaxel 75 mg/m2 i.v. every 3 weeks vs placebo i.v. plus docetaxel 75 mg/m2 i.v. every 3 weeks (pre-docetaxel)

mTOR Temsirolimus II Single-arm trial: temsirolimus 25 mg i.v. every 1 week, Change in circulating NCT00887640 (angiogenesis) plus anti-androgen upon progression (post-docetaxel) tumor cell counts over time

Everolimus II Single-arm trial: everolimus 10 mg orally daily plus Objective NCT00459186 docetaxel 75 mg/m2 i.v. every 3 weeks (pre-docetaxel) response rate

II Single-arm trial: everolimus 5 mg orally daily plus Time to disease NCT01051570 carboplatin AUC ¼ 5 i.v. every 3 weeks (post-docetaxel) progression

Ridaforolimus II Single-arm trial: ridaforolimus 50 mg i.v. every 1 week Objective NCT00110188 (post-docetaxel) response rate

PI3K BKM-120 II Single-agent trial: BKM-120 100 mg orally daily Progression-free Being planned (angiogenesis) (post-docetaxel) survival

S100A9 Tasquinimod III Randomized trial: tasquinimod 1 mg orally daily vs Progression-free NCT01234311 (angiogenesis) placebo daily (pre-docetaxel) survival

Clusterin Custirsen III Randomized trial: custirsen 640 mg i.v. every 1 week Overall survival NCT01188187 (apoptosis) plus docetaxel 75 mg/m2 i.v. every 3 weeks vs docetaxel 75 mg/m2 i.v. every 3 weeks (pre-docetaxel)

Prostate Cancer and Prostatic Diseases Emerging approaches for castration-resistant prostate cancer ES Antonarakis and AJ Armstrong 209 Table 1 Continued

Target/pathway Agent Phase Treatment arm(s) 1ary end point Identifier

III Randomized trial: custirsen 640 mg i.v. every 1 week Improvement NCT01083615 plus docetaxel 75 mg/m2 i.v. every 3 weeks vs in pain placebo i.v. every 1 week plus docetaxel 75 mg/m2 i.v. every 3 weeks (post-docetaxel)

Survivin YM-155 II Single-arm trial: YM-155 5 mg/m2 i.v. daily over 7 days X50% PSA k NCT00257478 (apoptosis) (post-docetaxel)

II Single-arm trial: YM-155 5 mg/m2 i.v. daily over 7 days Objective NCT00514267 plus docetaxel 75 mg/m2 i.v. every 3 weeks response rate (pre-docetaxel)

LY2181308 II Randomized trial: LY2181308 750 mg i.v. every 1 week Progression-free NCT00642018 plus docetaxel 75 mg/m2 i.v. every 3 weeks vs survival docetaxel 75 mg/m2 i.v. every 3 weeks (pre-docetaxel)

IGF-1R Cixutumumab II Randomized trial: cixutumumab 6 mg/kg i.v. every Progression-free NCT00683475 (cell nutrition) 1 week plus mitoxantrone 12 mg/m2 i.v. every 3 weeks survival vs ramucirumab (see above) 6 mg/kg i.v. every 1 week plus mitoxantrone 12 mg/m2 i.v. every 3 weeks (post-docetaxel)

II Single-arm study: cixutumumab 6 mg/kg i.v. every Time to disease NCT01026623 1 week plus temsirolimus 25 mg i.v. every 1 week progression

Figitumumab II Single arm trial: 20 mg/kg i.v. every Objective NCT00313781 3 weeks plus docetaxel 75 mg/m2 i.v. every 3 weeks response rate (pre- and post-docetaxel)

Src kinase Dasatinib III Randomized trial: dasatinib 100 mg orally daily plus Overall survival NCT00744497 (bone regulation) docetaxel 75 mg/m2 i.v. every 3 weeks vs placebo orally daily plus docetaxel 75 mg/m2 i.v. every 3 weeks (pre-docetaxel)

Saracatinib II Randomized trial: saracatinib 175 mg orally daily vs Change in bone NCT00558272 zoledronate 4 mg i.v. every 4 weeks resorption parameters (pre- or post-docetaxel)

KX2-391 II Single-arm trial: KX2-391 40 mg orally twice daily Time to disease NCT01074138 (pre-docetaxel) progression

HDAC (epigenetics) Panobinostat II Single-arm trial: panobinostat 15 mg/m2 i.v. on days 1 Progression-free NCT00667862 and 8 of a 21-day cycle (post-docetaxel) survival

DNMT (epigenetics) Azacitidine II Single-arm study: azacitidine 150 mg/m2 i.v. on days Objective NCT00503984 1–5 of a 21-day cycle plus docetaxel 75 mg/m2 i.v. response rate every 3 weeks (post-docetaxel)

PARP Olaparib II Single-arm study: olaparib 400 mg orally twice daily Objective NCT01078662 (DNA repair) (pre- or post-docetaxel) response rate

Veliparib II Single-arm study: veliparib 40 mg orally twice daily X30% PSA k NCT01085422 on days 1–7 of a 28-day cycle plus temozolomide 150 mg/m2 orally on days 1–5 of a 28-day cycle (post-docetaxel)

Abbreviations: AR, androgen receptor; AUC, area under the curve; CRPC, castration-resistant prostate cancer; CTLA-4, cytotoxic T lymphocyte-associated antigen-4; CYP17; cytochrome P450 17; DNMT, DNA methyltransferase; HDAC, histone deacetylase; IGF-1R, insulin-like growth factor receptor-1; i.v., intravenous; mTOR, mammalian target of rapamycin; PARP, poly (ADP-ribose) polymerase; PI3K, phosphoinositide 3-kinase; VEGF-R, vascular endothelial growth factor receptor. partial AR agonists, MDV3100 does not exhibit any (n ¼ 75) metastatic CRPC has been published recently.9 measurable agonistic activity. Finally, MDV3100 reduces In that trial, X50% PSA declines were seen in 62 and 51% translocation of the AR from the cytoplasm into the of chemotherapy-naı¨ve and taxane-pretreated patients, nucleus, blocking binding of the AR to androgen- objective tumor responses were observed in 36 and 12% response elements of DNA, with resultant tumoricidal of men and improvements in 18F- activity as opposed to the cytostatic activity that first- positron emission tomography imaging were noted in 67 generation anti-androgens exhibit in these model sys- and 40% of men. Radiographic progression-free survival tems8 (Figure 1). Notably, recent studies have shown the was 6.7 months in the docetaxel-pretreated patients and emergence of ligand-independent AR splice variants 417 months in chemotherapy-naı¨ve patients. In addi- in CRPC, some of which may also be inhibited by tion, 49% of all patients with unfavorable baseline MDV3100.7 circulating tumor cell (CTC) levels (X5 cells per 7.5 ml A phase I/II study of oral MDV3100 in men with of whole blood) converted to favorable CTC counts (o5 chemotherapy-naı¨ve (n ¼ 65) or taxane-pretreated cells) after MDV3100 treatment (including 75% of pre-

Prostate Cancer and Prostatic Diseases Emerging approaches for castration-resistant prostate cancer ES Antonarakis and AJ Armstrong

210 chemotherapy patients and 37% of post-chemotherapy or abiraterone treatment, men with previous abiraterone patients).9 Side effects of MDV3100 are generally mild, treatment and men with previous docetaxel treatment and include fatigue (27%) and nausea (9%). Rare seizures (Table 1). Additional therapeutic options indirectly (3/140 patients) have also been reported, perhaps targeting AR include inhibitors of tyrosine kinases that mediated by a direct effect of AR antagonism on central can directly activate AR signaling (for example, phos- nervous system g-aminobutyric acid-A receptors.10 phoinositide 3-kinase (PI3K), Src kinase, G-protein- A pivotal placebo-controlled double-blind phase III coupled receptors), inhibitors of chaperone proteins (for study (AFFIRM), randomizing 1170 patients with doc- example, heat-shock protein 90) and epigenetic agents etaxel-pretreated ketoconazole-naı¨ve CRPC to receive that may reduce AR transcriptional levels. Thus, addi- either MDV3100 160 mg daily (n ¼ 780) or placebo tional AR-directed therapies are on the horizon and (n ¼ 390), has now completed accrual (Table 1). This trial entering the clinic using a variety of approaches. has been powered to detect a 25% overall survival improvement with the use of MDV3100 compared with placebo. A second randomized phase III trial (PREVAIL) Immune checkpoint blockade in investigating the same treatment arms in men with chemotherapy-naı¨ve CRPC is currently underway, and metastatic CRPC has also been powered to detect a clinically relevant The autologous cellular immunotherapy, sipuleucel-T, survival improvement. If confirmed, these results may has been discussed previously in the first review of this suggest that more potent inhibitors of AR transcriptional two-part series. This review will outline an alternative activity may result in significant clinical benefits, even in immune-directed strategy: inhibition of immunological men who were deemed to be refractory to hormonal checkpoints. manipulations. In addition, one advantage of MDV3100 over agents such as abiraterone or orteronel is the lack of a need for concurrent corticosteroid administration. Ipilimumab However, the optimal sequencing of this agent, if Owing to ongoing host immunological pressures on approved, with immunotherapies and other emerging evolving tumors, have developed several hormonal therapies will need to be defined through mechanisms to escape immune surveillance, effectively future clinical trials. inducing a relative state of immune tolerance.16 One way to inhibit immunological evasion by tumor cells is through blockade of the immune checkpoint molecule Emerging AR-directed agents cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) Men with CRPC will inevitably develop disease progres- using monoclonal antibodies. CTLA-4 is a cell surface sion despite treatment with abiraterone/orteronel or protein found on tumor-infiltrating T lymphocytes that MDV3100. Possible resistance mechanisms to these functions as a negative regulator of T-cell activation, agents include further (second) mutations in the AR leading to attenuation of antitumor T-cell responses.17 In gene, truncated or alternatively spliced AR transcripts, murine prostate cancer models, CTLA-4 inhibition has constitutively activated AR, androgen synthesis by previously been shown to potentiate T-cell effects and CYP17-independent pathways and genetic changes induce tumor rejection as well as reduce metastatic in the CYP17A gene preventing its inhibition by recurrence after primary prostate tumor resection,18 abiraterone/orteronel.11 To overcome such resistance providing evidence that immune checkpoint blockade mechanisms and to produce sustained inhibition of may be a useful approach. AR-dependent signaling, CYP17 inhibitors and second- Several clinical trials using the anti-CTLA-4 antibody, generation anti-androgens may have to be used in ipilimumab, have been conducted in men with meta- combination with each other (or with additional targeted static CRPC. These include phase I and II studies of agents such as those discussed below), more potent ipilimumab monotherapy or in combination with radia- analogs of both agents may have to be developed such as tion,19,20 as well as a phase I dose-escalating study inhibitors of the N-terminal transcriptional activation combining ipilimumab with granulocyte–macrophage- domain of AR12 or agents with dual CYP17-inhibitory colony-stimulating factor.21 Encouragingly, X50% PSA and AR-blocking properties may have to be identified. reductions were observed in about 20% of patients and To this end, TOK-001 is a novel oral agent with radiological tumor responses were seen in about 5% of structural similarity to abiraterone.13 However, in addi- men. Another phase I study testing the combination tion to inducing potent CYP17 (C17,20-lyase) inhibition, of ipilimumab with a granulocyte–macrophage-colony- this compound has AR antagonistic activity and also stimulating factor-secreting allogeneic cellular prostate causes downregulation of AR protein expression14 cancer immunotherapy (GVAX) also showed X50% PSA (Figure 1). TOK-001 is currently being evaluated in a responses (in 33% of men) and a few objective clinical phase I/II clinical trial (ARMOR1) in men with meta- responses (8% of men) at upper dose levels.22 These static chemotherapy-naı¨ve CRPC who have not received results are particularly worth noting, because bonafide previous ketoconazole (Table 1). PSA and tumor responses were rarely reported in the Finally, ARN-509 is a novel oral anti-androgen that is a immunotherapy trials discussed in the previous review structural analog of MDV3100 optimized for sensitivity (for example, using sipuleucel-T or Prostvac-VF). Com- to prostate cancers with overexpressed AR, and showing mon side effects of ipilimumab include fatigue (42%), greater potency and efficacy than MDV3100 in preclinical nausea (35%), pruritus (24%), constipation (21%) and experiments15 (Figure 1). ARN-509 is now being studied rash (19%). In addition, because in a normal host CTLA-4 in a phase I/II clinical trial allowing enrollment of three serves to attenuate autoimmunity, immunological CRPC populations: men without previous docetaxel toxicities resulting from an unchecked and overly

Prostate Cancer and Prostatic Diseases Emerging approaches for castration-resistant prostate cancer ES Antonarakis and AJ Armstrong exuberant immune response may occur. Such severe type. Custirsen is a novel intravenously administered 211 immune-related adverse events include autoimmune antisense oligonucleotide moiety that inhibits clusterin colitis (8%), adrenal insufficiency (2%), hepatitis (1%), at the mRNA level (Figure 1), increasing sensitivity and even hypophysitis (1%).23 to androgen deprivation as well as chemotherapy To investigate the effect of ipilimumab on overall in prostate cancer cell lines and xenograft models.30,31 survival, a multicenter placebo-controlled randomized In a randomized phase II study of docetaxel with or phase III study in docetaxel-refractory CRPC has been without custirsen in 82 patients with metastatic CRPC, launched, which aims to examine the combination of PSA responses (58 vs 54%) as well as progression-free ipilimumab and radiation therapy in men with bone survival (7.3 vs 6.1 months) were similar in both arms. metastases (Table 1). A total of 800 patients will first However, overall survival trended in favor of the receive palliative radiation therapy to a bone lesion, and combination arm (23.8 vs 16.9 months, P ¼ 0.06), will then be randomized (1:1) to intravenous ipilimumab although survival was not the primary end point of this or placebo infusion given every 3 weeks. This trial is study and confidence intervals around these estimates somewhat innovative in that it incorporates low-dose were wide and potentially confounded by subsequent radiotherapy before immunotherapy in an effort to therapies.32 Adverse events associated with custirsen prime an antitumor immune response against all sites included fatigue (480%), fever (30–50%), rigors (40–60%), of metastatic disease through release of antigen from diarrhea (40–60%) and rash (20–40%). Another phase II irradiated tumor cells. A second double-blind rando- study of second-line chemotherapy plus custirsen in mized phase III study comparing ipilimumab mono- patients with docetaxel-pretreated CRPC has recently therapy against placebo in 600 patients with completed accrual, and survival outcomes are awaited. chemotherapy-naı¨ve metastatic CRPC is now underway, Finally, a registrational placebo-controlled phase III and has also been powered to detect an overall survival study of docetaxel retreatment with or without custirsen improvement with ipilimumab (Table 1). for the second-line management of men with docetaxel- Encouragingly, a phase III trial in patients with refractory disease was recently launched (Table 1); metastatic has recently shown a survival overall survival was chosen as the primary end point advantage with the use of ipilimumab,24 providing a in this trial. However, the recent approval of cabazitaxel proof of principle that CTLA-4 blockade may have merit and changing standards of care call into question the in human cancers and resulting in the Food and Drug value of docetaxel retreatment in all but a select group of Administration approval of this agent for metastatic men in this setting. melanoma. Thus, CTLA-4 blockade and other immune Another class of drugs mediating their effect via the checkpoint blockades (such as PD-1 antagonism)25 are apoptotic pathway is the survivin antagonists. Survivin, emerging as potential therapeutic strategies in CRPC, in one of the most cancer-specific proteins ever identified, which the overall risk–benefit ratio of induced auto- has been shown to inhibit apoptosis as well as to enhance immunity vs antitumor activity will need to be evaluated cell proliferation and promote tumor angiogenesis in carefully in the context of controlled clinical trials in multiple tumor types including prostate cancer.33 these men who are generally older and more heavily Because of its marked upregulation in malignant tissues pre-treated than melanoma patients. but not in normal cells, and the observation that its suppression leads to inhibition of tumor growth, survivin has attracted attention as a promising target for anticancer therapies. Alternative targeted approaches for Two agents in this class are currently in clinical metastatic CRPC development. The first is LY-2181308 (an antisense oligonucleotide that binds to survivin mRNA)34 and Although AR-dependent signaling almost always occurs the second is YM-155 (a small-molecule survivin in CRPC, there can be substantial heterogeneity in the 35 26 inhibitor). Several phase II studies investigating these intensity of this AR signaling. Prostate cancers with two drugs in men with metastatic CRPC are now lower AR activity or those exposed to prolonged periods underway or have recently completed accrual (Table 1). of androgen suppression may show upregulation of other oncogenic pathways, including Src kinase, cluster- in, epithelial–mesenchymal transition pathways, PI3K, Src kinase signaling c-MET and others. Numerous drugs inhibiting alterna- Src is a non-receptor signal-transduction tive pathways that have crosstalk with AR-dependent protein that is important in tumor cell proliferation, pathways have been evaluated in clinical trials. Here, we migration, angiogenesis, survival and transition to the will focus on selected promising agents that are currently castration-resistant state.36 Src also controls normal and being investigated in phase II and III studies (Figure 1). abnormal osteoclastic activity, and has been implicated in development and progression of bone metastases.37 Dasatinib is an oral inhibitor of multiple oncogenic Apoptosis kinases including Src. In experimental models, dasatinib Clusterin is a stress-induced antiapoptotic chaperone suppressed proliferation of prostate cancer cell lines,38 protein expressed in various cancers including prostate and inhibited adhesion, migration and invasion.39 In cancer,27 and has received renewed attention due to the addition, dasatinib reduced tumor growth and lymph development of an antisense inhibitor to this protein. node involvement in a prostate cancer mouse xenograft Importantly, expression of clusterin in prostate tumors model.40 A phase II study of single-agent dasatinib in increases after treatment with androgen ablation or men with metastatic CRPC did not show significant PSA chemotherapy,28,29 conferring a more resistant pheno- responses, but 19% of patients were free of disease

Prostate Cancer and Prostatic Diseases Emerging approaches for castration-resistant prostate cancer ES Antonarakis and AJ Armstrong

212 progression at 6 months. In addition, more than half of (B10%), but had minimal effect on PSA levels in men subjects had X40% declines in urinary N-telopeptide with both chemotherapy-naı¨ve and docetaxel-pretreated levels (a marker of bone resorption), and 60% showed CRPC.51,52 In addition, a single-arm study of docetaxel reductions in bone alkaline phosphatase.41 In a separate plus showed tolerability and a reasonable phase I/II study combining dasatinib with docetaxel in a degree of clinical activity in the front-line setting (39% similar patient population, PSA responses were observed objective response rate), with over 90% of men surviving in 57% of participants, objective radiographic responses 1 year.53 However, a definitive randomized phase III were seen in 60% of men and 30% of patients with bone study comparing single-agent sunitinib vs placebo in metastases showed amelioration in bone scans.42 A large patients with docetaxel-refractory disease completed placebo-controlled randomized phase III study evaluat- accrual of over 800 patients, and was found not to confer ing this combination in 1500 men with metastatic an overall survival improvement.54 This result suggests chemotherapy-naı¨ve CRPC is now underway (Table 1), that single-agent anti-VEGFR- or platelet-derived growth and will examine overall survival as its primary end factor receptor-based therapies may be insufficient to point. Adverse effects of dasatinib include diarrhea promote clinical benefit. Importantly, exploring the (62%), nausea (47%), fatigue (45%) and fluid retention activity of these VEGF tyrosine kinase inhibitors in (21%). Newer Src kinase inhibitors, such as saracatinib43 combination with established cytotoxic and immune- and KX2-391,44 are in earlier stages of clinical develop- modulatory or hormonal therapies remains of great ment in patients with metastatic CRPC (Table 1). interest, given the potential for synergy when combining these agents. Finally, a novel oral VEGFR tyrosine kinase inhibitor, cediranib,55 is currently being tested in a phase Angiogenesis II study where it is being administered with or without Tumor angiogenesis is thought to have an important role the Src inhibitor dasatinib in patients with metastatic in prostate cancer maintenance and progression, and docetaxel-refractory CRPC (Table 1). Adverse events elevated plasma levels of vascular endothelial growth related to the use of these tyrosine kinase inhibitors factor (VEGF) have been correlated with advanced include fatigue (30–50%), nausea (20–40%), hypertension clinical stage and decreased survival.45 In addition, (15–25%), diarrhea (30–50%), hand–foot syndrome (20–30%), antibodies to VEGF slow tumor proliferation in prostate rash (25–40%) and congestive heart failure (rare). cancer xenograft models, especially when combined with Another target that has received recent attention is chemotherapy.46 However, despite strong preclinical the MET protein, a transmembrane receptor whose only rationale, a phase III randomized study in men with known ligand is . Aberrant chemotherapy-untreated CRPC (CALGB 90401) failed to activation or overexpression of MET is a common event show a survival advantage with the anti-VEGF antibody in prostate cancer (especially in castration-resistant bone when combined with docetaxel compared metastases), and is associated with proliferation, inva- with docetaxel used alone (22.6 vs 21.5 months), sion and angiogenesis.56,57 Moreover, androgen suppres- although significant improvements were seen with sion has been shown to induce increased MET respect to PSA responses (70 vs 58%) and radiographic expression.58 (XL184) is an oral potent responses (53 vs 42%), as well as progression-free inhibitor of MET and VEGFR that has shown robust survival (9.9 vs 7.5 months).47 However, these results antiangiogenic, antiproliferative and anti-invasive activ- do not indicate that antiangiogenic therapies may never ity in preclinical systems.59 Preliminary results from a have a role in the treatment of CRPC, as much of this phase II study in men with metastatic CRPC with up to failure may be explained by an imbalance of treatment- one previous chemotherapy revealed objective responses related toxicities (cardiovascular events, neutropenic in 10% of patients with measurable soft-tissue disease, complications) in this older population with multiple and improvements in bone scans in a remarkable 95% of co-morbidities. To this end, it was reported that the men with osseous metastases, which was often accom- presence and number of co-morbidities (for example, panied by pain improvements.60 Toxicities with this cardiovascular disease, hypertension, diabetes, renal agent include fatigue (67%), diarrhea (55%), anorexia disease, liver disease) among patients in the CALGB (51%), emesis (44%) and hypertension (22%). Although 90401 trial significantly correlated with survival, and that the 12-week success rates, particularly in the bone, are there was an increase in the average number of co- strikingly high (including some complete resolutions of morbidities in the docetaxel–bevacizumab arm.48 Future skeletal abnormalities as visualized on bone scan), the development of this and other antiangiogenic agents lack of robust PSA responses and the uncertainty over may rely on combinations with other classes of angio- the durability of these results as measured by progres- genesis inhibitors or other chemotherapeutic drugs sion-free survival will require confirmatory controlled whose toxicities do not overlap, and will require careful trials to assess the overall clinical benefit of this agent as patient selection for those men most likely to benefit and well as the appropriate dose for long-term use. As the not be harmed by this class of agents. prostate cancer landscape is changing rapidly, the An alternative approach has focused on tyrosine evaluation of cabozantinib in the post-cabazitaxel and kinase inhibitors, agents that block angiogenic trans- post-abiraterone setting against prednisone or best membrane receptors such as the VEGF receptor (VEGFR) supportive care would be one such approach to the (Figure 1). In phase II studies involving men with rapid evaluation of clinical benefit of this novel dual metastatic CRPC, oral sorafenib was shown to prevent MET/VEGFR2 inhibitor. Further investigation of this radiological progression and even caused regression of agent’s activity in the bone using novel imaging techniques bone metastases in some patients (o10%), but did not (18F-positron emission tomography) or pharmacodynamic induce significant PSA responses.49,50 Similarly, oral studies should also be considered to further understand sunitinib produced some partial radiographic responses how this agent is controlling metastatic disease.

Prostate Cancer and Prostatic Diseases Emerging approaches for castration-resistant prostate cancer ES Antonarakis and AJ Armstrong

A final angiogenesis-inhibiting agent that has received and also as maintenance therapy after responding to 213 renewed attention is the oral quinoline derivative docetaxel treatment.76 A third mTOR inhibitor, ridafor- tasquinimod (Table 1). Although the antiangiogenic olimus, is also being investigated in the phase II setting properties of this agent have been amply shown in as monotherapy in men with taxane-refractory CRPC several in vitro and in vivo prostate cancer models,61 the (Table 1). Toxicities of mTOR agents include maculopap- exact mechanism of action of this drug remains elusive ular rash (20–40%), hypertriglyceridemia (40–70%), and appears to be unrelated to VEGFR inhibition. hyperglycemia (30–60%), allergic reactions (3–5%), pedal However, one proposed action of tasquinimod involves edema (15–30%), mucositis (40–60%), pneumonitis inhibition of S100A9, a -binding protein involved (5–10%) and thrombocytopenia (20–40%). in cell cycle progression and differentiation as well as An alternative strategy focuses on directly inhibiting recruitment of tumor-infiltrating myeloid-derived sup- proximal mediators of the mTOR pathway, such as PI3K pressor cells.62 Impressively, a randomized double-blind or Akt. To this end, advanced prostate cancers frequently placebo-controlled phase II study involving 200 patients show activation of PI3K and Akt,77,78 and this activation with chemotherapy-naı¨ve metastatic CRPC met its has correlated with recurrent disease following prosta- primary end point and showed that patients receiving tectomy.79 In addition to promoting cell survival through oral tasquinimod had a median progression-free survival the inhibition of apoptosis, the PI3K/Akt pathway of 7.6 vs 3.2 months in those receiving placebo regulates cell growth, proliferation and angiogenesis via (P ¼ 0.001).63 Adverse events with this agent included mTOR, and facilitates translation of signals such as c-Myc, gastrointestinal disorders (40%), fatigue (23%), muscu- hypoxia-inducible factor, cyclin D and VEGF.80 Interest- loskeletal pain (12%) and asymptomatic elevations of ingly, PI3K may also contribute to stemness in prostate pancreatic enzymes and inflammatory markers. Rare but cancer, leading to accelerated tumor-initiating potential serious toxicities were heart failure (1%), myocardial and invasiveness, as well as resistance to current thera- infarction (1%), stroke (1%) and deep vein thrombosis pies.81 Given this preclinical data, there are a number of (4%). A multi-center randomized phase III trial of agents entering the clinic with activity against the PI3K/ tasquinimod vs placebo in patients with chemotherapy- Akt pathway that are now being tested in men with CRPC. untreated metastatic CRPC has been launched. A detailed discussion of this topic is beyond the scope of this review, and a number of excellent recent reviews have been published on this topic.64,82 PI3K/Akt/mTOR pathway BKM-120 is an oral pan-PI3K inhibitor that lacks direct Given the high prevalence of phosphatase and tensin mTOR kinase inhibitory effects83 (Figure 1). A phase II homologue deleted on chromosome ten (PTEN) loss and study using BKM-120 in men with docetaxel-refractory PI3K pathway activation in metastatic prostate cancer, metastatic CRPC will soon be launched (Table 1) through the development of agents that target components of this the Department of Defense Prostate Cancer Consortium important oncogenic survival pathway has focused to investigate the clinical activity of PI3K inhibition in initially on men with metastatic CRPC.64 One critical this disease as well as potential pharmacodynamic component has been the TORC1 pathway, an important predictors of benefit. Other PI3K, dual PI3K-TORC1/2 gatekeeper protein that regulates extracellular and and Akt inhibitors are also in early stages (phases I nutrient-based signaling with the metabolic programs and II) of drug development in CRPC and other solid and energy outputs of many cells including malignant tumors.64 Toxicities of these agents have included prostate cancer cells.65 Although mammalian target of hyperglycemia (20–40%), rash (10–20%), mood changes rapamycin (mTOR or TORC1) inhibitors may have (10–20%) and fatigue (20–30%).83,84 The development of modest single-agent activity in advanced CRPC,66,67 strategies to identify pretreatment biomarkers (that is, the combination of these drugs with docetaxel is from tumor specimens, specialized imaging or CTCs) attractive given their ability to reverse or delay chemo- that may predict which men are likely to benefit from therapy resistance in prostate cancer cell lines.68,69 In PI3K inhibitors will be essential in the rational develop- addition, these agents induce apoptosis when combined ment of these agents. with chemotherapy in patients who have activation of the Akt pathway as a result of PTEN mutation/loss or other genetic alteration.70 Limitations of the use of single-agent Insulin-like growth factor receptor-1 pathway TORC1 inhibitors have included feedback upregulation of Insulin-like growth factor receptor-1 (IGF-1R) and its upstream survival signals (such as PI3K and growth factor ligands may have an important role in prostate carcino- receptor levels) as well as the lack of induction of genesis through mechanisms that involve mitogenesis, apoptosis or prolonged cytostasis owing to parallel antiapoptosis and cellular transformation (Figure 1). activation of alternate oncogenic pathways.67,71,72 Moreover, IGF-1R is often overexpressed in prostate Several mTOR inhibitors have entered human clinical tumors and can mediate cell proliferation and resistance testing in combination with other agents (Figure 1). One to androgen ablation.85,86 Therapeutic monoclonal anti- of these, everolimus, is currently being evaluated in bodies that bind to the extracellular domain of IGF-1R combination with docetaxel for the first-line treatment of can potently inhibit the function of this receptor. In metastatic CRPC,73 and is also being used in combination prostate cancer cell lines and in xenograft models, such with carboplatin for the treatment of docetaxel-refractory antibodies have been shown to inhibit growth of both disease (Table 1). In addition, temsirolimus and ever- androgen-dependent and -independent tumors.87,88 olimus are being tested in combination with anti- Cixutumumab is an intravenous fully human immu- androgen therapy in men with chemotherapy-naı¨ve noglobulin G1 that specifically CRPC (based on preclinical studies showing synergistic targets IGF-1R, inhibiting ligand binding and IGF activity of anti-androgens with mTOR inhibitors),74,75 signaling.89 In a phase II study of cixutumumab in men

Prostate Cancer and Prostatic Diseases Emerging approaches for castration-resistant prostate cancer ES Antonarakis and AJ Armstrong

214 with metastatic CRPC, 29% of patients showed stable dine included fatigue (41%) and neutropenia (18%). disease for 6 months, whereas a similar percentage Another phase II study evaluating the combination of experienced PSA responses.90 Toxicities with this agent docetaxel and azacitidine in men with docetaxel- included fatigue (20–30%), hyperglycemia (15–25%), pretreated CRPC is now underway (Table 1). thrombocytopenia (10–20%), hyperkalemia (5–10%) and muscle spasms (10–20%). A phase II study combining cixutumumab with mitoxantrone compared with ramu- PARP inhibition cirumab (an anti-VEGFR2 monoclonal antibody) with PARPs are a family of enzymes that mend single-strand mitoxantrone in men with docetaxel-refractory meta- DNA breaks through the repair of base excisions static CRPC has completed accrual and results are (Figure 1). PARP inhibition leads to accumulation of anticipated soon (Table 1). single-strand DNA breaks that, if left unchecked, lead Figitumumab is a second fully human anti-IGF-1R to double-strand DNA breaks at replication forks.102 immunoglobulin G2 monoclonal antibody that has ente- 91 These double-strand breaks are repaired by homologous red clinical testing. In a phase Ib study of intravenous recombination, mediated in part by the tumor suppres- figitumumab given in combination with docetaxel to men sor proteins BRCA1 and BRCA2. Preclinical studies have with metastatic CRPC, 22% of patients had objective shown that BRCA1/2 mutation combined with PARP tumor responses and 67% had disease stabilization lasting inhibition creates a ‘synthetic lethality’ for such cells.103 X 92 6months. In addition, 90% of patients with measur- This results in exquisite sensitivity of BRCA1/2 mutant X able CTC levels at baseline achieved 30% reductions in cells to PARP inhibitors. Another group of tumors that CTC counts after treatment. Toxicities of this combination show increased sensitivity to PARP inhibition are those regimen were leucopenia (including neutropenia) (20%), that harbor PTEN loss, a frequent phenomenon in CRPC. fatigue (50%), diarrhea (25%) and hyperglycemia (10%). A To this end, PTEN-null tumors exhibit genomic instabil- randomized phase II study of figitumumab combined ity due to downregulation of Rad51 and impaired with docetaxel in men with chemotherapy-naı¨ve (arm A) homologous recombination, or due to defects in cell and docetaxel-refractory (arm B) CRPC has completed cycle checkpoints.104 accrual and results are awaited (Table 1). Olaparib was the first PARP inhibitor to reach human clinical testing (Figure 1). In a phase I study of oral olaparib in patients with BRCA1/2-mutated tumors, this Epigenetic therapies agent produced notable responses in several subjects Histone deacetylases are regulators of histone acetylation including a 450% PSA drop with resolution of bone status, which is critical for androgen receptor-mediated metastases in a man with BRCA2-related CRPC.105 transcriptional activation of genes governing cell survi- 93 Toxicities of olaparib include gastrointestinal disturbance val, proliferation, differentiation and apoptosis (Fig- (40%), fatigue/somnolence (30%), lymphopenia (5%) ure 1). Vorinostat is an oral histone deacetylase inhibitor and thrombocytopenia (5%). A larger phase II study of that has shown antitumor activity in prostate cancer cell 94 olaparib in patients with advanced BRCA1/2-mutated lines as well as animal models. However, a phase II cancers is ongoing (Table 1). However, the success of study of vorinostat monotherapy in men with docetaxel- PARP inhibitors in CRPC patients will rely on the refractory CRPC did not show significant PSA or identification of biomarkers of sensitivity to these agents radiological responses and was associated with a high outside of the traditional germline BRCA1/2 mutations, frequency of adverse events including fatigue (80%), 95 including PTEN loss or somatic or alternative genetic or emesis (75%), diarrhea (35%) and weight loss (25%). A epigenetic alterations in DNA repair enzymes. second histone deacetylase inhibitor, panobinostat (used Another important property of PARP inhibitors is their both as an oral and intravenous agent), has completed 96,97 ability to enhance the activity of DNA-damaging phase I testing in combination with docetaxel; the cytotoxic agents (for example, alkylators, platinum intravenous formulation has been chosen for future compounds and topoisomerase inhibitors).106 To this development. Side effects of panobinostat include nausea end, addition of the PARP inhibitor veliparib (ABT-888) (75%), diarrhea (50%), thrombocytopenia (50%) and to temozolomide potentiates the antineoplastic effects fatigue (38%). A phase II trial of single-agent IV of the alkylating agent in several cancer cell lines and panobinostat in docetaxel-refractory disease is currently animal xenograft models.107 This has provided the ongoing (Table 1). rationale for conducting a single-arm phase II study DNA methylation of important tumor suppressor examining the combination of oral veliparib and oral genes represents another epigenetic mechanism by temozolomide in men with metastatic CRPC who have which prostate cancer may progresses to a castration- 98 progressed after 1–2 previous (Table 1). resistant state. The hypomethylating agent azacitidine Adverse events with veliparib are minimal, and no dose- (Figure 1) is a subcutaneously administered drug that limiting toxicities were reported in phase I trials. Finally, a exerts its antineoplastic effects by inhibiting DNA randomized phase II cooperative group trial of carboplatin methyltransferases in promoter regions of genes, leading 99 and paclitaxel with or without veliparib in the second-line to reversal of gene silencing. In preclinical prostate treatment of metastatic CRPC is being planned. cancer models, azacitidine reverses resistance to andro- gen ablation and chemotherapy,100 making this agent attractive for clinical trial development. To this end, a phase II study of azacitidine in men with chemotherapy- Conclusion naı¨ve CRPC induced lengthening of PSA doubling times in 56% of patients and resulted in a median progression- With more drugs at our fingertips for the treatment of free survival time of 12.4 weeks.101 Toxicities of azaciti- metastatic CRPC than ever before, and an increasing

Prostate Cancer and Prostatic Diseases Emerging approaches for castration-resistant prostate cancer ES Antonarakis and AJ Armstrong 215 number of novel therapeutic targets being discovered 2 Hanahan D, Weinberg RA. Hallmarks of cancer: the next every day, we are still left with several challenges and generation. Cell 2011; 144: 646–674. unanswered questions. First, we must determine how 3 Matsunaga N, Kaku T, Ojida A, Tanaka T, Hara T, Yamaoka M these approved and experimental therapies should et al. C(17,20)-lyase inhibitors: design, synthesis and structure– ideally be sequenced in individual patients with CRPC. activity relationships of (2-naphthylmethyl)-1H-imidazoles For example, should sipuleucel-T routinely be given as novel C(17,20)-lyase inhibitors. Bioorg Med Chem 2004; 12: 4313–4336. before chemotherapy? Should abiraterone be reserved 4 Vasaitis TS, Bruno RD, Njar VC. CYP17 inhibitors for prostate only for docetaxel-refractory patients? Second, we will cancer therapy. 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In addition, can PTEN 7 Watson PA, Chen YF, Balbas MD, Wongvipat J, Socci ND, Viale et al. loss predict benefit from PI3K or PARP inhibitors? A Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full- Ultimately, only prospective trials incorporating biomar- length androgen receptor. Proc Natl Acad Sci USA 2010; 107: ker-driven hypotheses will be able to address these 16759–16765. important clinical questions. Thus, the collection of 8 Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V et al. tumor specimens or correlative samples may be essential Development of a second-generation for treat- in identifying novel targets or developing enrichment ment of advanced prostate cancer. Science 2009; 324: 787–790. strategies for future study of these agents. 9 Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou Third, we must design smarter trials with the aim of E et al. Antitumour activity of MDV3100 in castration-resistant quickly yet reliably identifying agents that do not hold prostate cancer: a phase 1–2 study. Lancet 2010; 375: 1437–1446. promise, while enabling those that do to move swiftly 10 Foster WR, Car BD, Shi H, Levesque PC, Obermeier MT, Gan J to registrational studies. For example, in the clinical et al. Drug safety is a barrier to the discovery and development of new androgen receptor antagonists. Prostate 2011; 71: development of MDV3100, a pivotal phase III trial was 480–488. designed directly following an initial phase I/II study 11 Attard G, Cooper CS, de Bono JS. Steroid hormone receptors in that showed significant drug activity in men with CRPC. prostate cancer: a hard habit to break? Cancer Cell 2009; 16: 458–462. Finally, we must select our patients more carefully based 12 Sadar MD. Small molecule inhibitors targeting the ‘Achilles heel’ on clinical or molecular characteristics, to identify the of androgen receptor activity. Cancer Res 2011; 71: 1208–1213. subset most likely to benefit from a particular therapy. 13 Handratta VD, Vasaitis TS, Njar VC, Gediya LK, Kataria R, For example, in men with significant pain, perhaps Chopra P et al. Novel C-17-heteroaryl steroidal CYP17 sipuleucel-T is not appropriate systemic therapy given inhibitors/: synthesis, in vitro biological activity, the prolonged onset of action and lack of palliative pharmacokinetics, and antitumor activity in the LAPC4 benefits; in addition, immune-based biomarkers may human prostate cancer xenograft model. J Med Chem 2005; 48: 2972–2984. shed light on which men may obtain a greater degree of 14 Vasaitis T, Belosay A, Schayowitz A, Khandelwal A, Chopra P, benefit from these immunotherapies. However, despite Gediya LK et al. Androgen receptor inactivation contri- these and other unresolved issues, continued advances butes to antitumor efficacy of 17{alpha}-hydroxylase/17,20-lyase in our understanding of prostate cancer biology and inhibitor 3beta-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5, genomics will certainly further expand our armamentar- 16-diene in prostate cancer. Mol Cancer Ther 2008; 7: 2348–2357. ium of treatment options for patients with CRPC moving 15 Sawyers CL. New insights into the prostate cancer genome forward. Although the future looks bright, we must and therapeutic implications. Proceedings of the Prostate Cancer continue to combine good science with innovative Foundation Annual Scientific Retreat, Washington, DC, 2010. drug development strategies to successfully chart this 16 Drake CG, Jaffee E, Pardoll DM. Mechanisms of immune course. evasion by tumors. Adv Immunol 2006; 90: 51–81. 17 Hodi FS. Cytotoxic T-lymphocyte-associated antigen-4. Clin Cancer Res 2007; 13: 5238–5242. 18 Kwon ED, Foster BA, Hurwitz AA, Madias C, Allison JP, Greenberg NM et al. Elimination of residual metastatic prostate Conflict of interest cancer after surgery and adjunctive cytotoxic T lymphocyte- associated antigen 4 (CTLA-4) blockade immunotherapy. Proc Dr Antonarakis declares no conflicts of interest. Natl Acad Sci USA 1999; 96: 15074–15079. Dr Armstrong has served as a consultant for Novartis 19 Small EJ, Tchekmedyian NS, Rini BI, Fong L, Lowy I, Allison JP. and Amgen; he is on the speakers bureau for / A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in Wyeth, Dendreon, and sanofi-aventis; and he has patients with hormone-refractory prostate cancer. Clin Cancer received research funding from Bristol-Myers Squibb, Res 2007; 13: 1810–1815. Imclone, Pfizer/Wyeth, Active Biotech, Medivation, 20 Beer TM, Slovin SF, Higano CS, Tejwani S, Dorff TB, Dendreon, Novartis and sanofi-aventis. Stankevichet E et al. Phase I trial of ipilimumab alone and in combination with radiotherapy in patients with metastatic castration resistant prostate cancer. J Clin Oncol 2008; 26 (Suppl): abstract 5004. References 21 Fong L, Kwek SS, O’Brien S, Kavanagh B, McNeel DG, Weinberg V et al. Potentiating endogenous antitumor immunity 1 Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA to prostate cancer through combination immunotherapy with Cancer J Clin 2010; 60: 277–300. CTLA4 blockade and GM-CSF. Cancer Res 2009; 69: 609–615.

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