Recent advances revolutionize treatment of metastatic prostate cancer

1133102217FON1365 ISSN 1479-6694Future Oncol (2013) 9(8) 1133ndash1144

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In 2004 docetaxel became the first chemo-therapy agent to extend survival for men with metastatic castration-resistant prostate cancer (mCRPC) [12] While docetaxel was a signifi-cant advance in the treatment of mCRPC ensu-ing years brought no additional novel therapies Numerous studies evaluated docetaxel-based combinations andor emerging targeted molec-ular therapies to no avail These included trials with sunitinib sorafenib zibotentan dasatinib calcitriol bevacizumab and aflibercept alone or in combination with docetaxel [3ndash9] Failure to show enhanced clinical benefit in spite of addi-tional potential toxicity has limited the enthusi-asm for such trials Not until 2010 was cabazi-taxel another taxane found to improve survival in patients who had already been treated with docetaxel Although cabazitaxel became the first second-line therapy to improve survival for men with mCRPC enthusiasm for cabazitaxel was tempered by the level of neutropenia seen in study patients and by the 5 of patients who died from neutropenia-related complications [10] Hopes were raised again by modern hormonal thera-pies and immunotherapies which many believe will revolutionize the treatment of mCRPC and herald an era of significant changes in the treat-ment of a disease that affects almost a quarter of a million men in the USA each year [11]

Hormonal therapySince the breakthrough discovery of Huggins and Hodges in the 1940s establishing the andro-gen dependence of prostate cancer proliferation

androgen deprivation has been foundational in the management of metastatic prostate cancer [12] Androgen deprivation can be achieved sur-gically by orchiectomy medically by an LHRH agonist such as leuprolide or by a combination of a LHRH agonist plus an androgen receptor antagonist (ARA) for example bicalutamide (Casodexreg AstraZeneca London UK) for complete androgen blockade Despite initial response rates of 80ndash90 virtually all men progress to androgen-insensitive disease When anti-androgen withdrawal fails one therapeutic option is the use of an alternative ARA as sec-ond-line hormonal therapy [1314] The first gen-eration of nonsteroidal anti-androgens approved by the US FDA includes flutamide (Eulexinreg Schering-Plough NJ USA) bicalutamide and nilutamide (Nilandronreg Sanofi-Aventis Paris France) These bind to the androgen recep-tor (AR) and inhibit the stimulatory action of testosterone and dihydrotestosterone the pri-mary androgen that stimulates the growth of prostate tissue including prostate cancer It is unclear why some patients with castrate levels of testosterone respond to a second ARA after initial progression but it is presumed that spe-cific anti-androgens interact differently with the AR on prostate cancer cells [15] Our grow-ing understanding of the function of andro-gens and ARs has led to the development of new therapeutic agents some of which target the AR with greater affinity than first-genera-tion ARAs Others block androgen synthesis not only in the testes and adrenal glands but

Recent advances revolutionize treatment of metastatic prostate cancer

Ravi A Madan1 amp Philip M Arlen1

1Medical Oncology Branch Center for Cancer Research National Cancer Institute National Institute of Health Bethesda MD USA Author for correspondence arlenpmailnihgov

In 2004 the chemotherapy agent docetaxel was approved for the treatment of metastatic prostate cancer Although it has taken almost a decade significant new advances have been made in this area including the clinical development of modern hormonal therapies such as abiraterone and enzalutamide and immunotherapies such as sipuleucel-T all of which have improved survival in metastatic prostate cancer These agents have not only provided new therapeutic options for patients with advanced disease they have also spurred research in both androgen receptor-targeting therapy and immunotherapy Future trials will focus on the optimal sequence of these and other emerging therapies with the aim of using these treatments earlier in the disease course (including the adjuvant setting) to enhance clinical benefit and potentially increase the cure rate for prostate cancer

Keywords

n castration resistant n hormone therapy n immunotherapy n metastatic prostate cancer

Revie

wFor reprint orders please contact reprintsfuturemedicinecom

Future Oncol (2013) 9(8)1134 future science group

also in the tumor These recent developments (Table 1) have led to the approval of the ARAs abiraterone and enzalutamide both of which have significantly improved overall survival (OS) compared with placebo in Phase III tri-als in patients with castration-resistant prostate cancer (CRPC)

AbirateroneAdministered orally abiraterone irreversibly inhibits the products of the CYP17 gene includ-ing both 1720 lyase and 17-a-hydroxylase [1617] Through this mechanism of action abiraterone blocks the synthesis of androgens in the tumor testes and adrenal glands The toxicity profile of abiraterone depends on the mechanism of action Inhibition of 17-a-hydroxylase can result in decreased cortisol levels and a compensatory rise in adrenocorticotropic hormone (ACTH) level which is mediated by a hypothalamic response to partial adrenal inhibition Increased release of ACTH can cause increased produc-tion of adrenal mineralocorticoid producing both hypertension and hypokalemia However when abiraterone is given without concomitant glucocorticoids patients typically do not experi-ence clinical adrenal insufficiency since cortisol production is preserved The effects of mineralo-corticoid excess can be attenuated by coadmin-istration of prednisone which reduces ACTH-mediated stimulation of the adrenal glands

The clinical benefit of abiraterone was first observed in a Phase III trial in men with mCRPC

who had received prior docetaxel [1819] In this study 1195 men were randomized 21 to receive either abiraterone at 1000 mgday with oral pred-nisone two-times 5 mgday or a placebo with prednisone as a control Treatment continued until disease progression The study was termi-nated when results of an interim ana lysis exceeded prespecified criteria The final ana lysis of OS was conducted at a median follow-up of 20 months There was an increase in OS for patients ran-domized to abiraterone (median 158 months) compared with patients in the placebo arm (median 112 months) Statistically significant improvements were also seen in time to PSA pro-gression (85 vs 66 months) radiologic progres-sion-free survival (56 vs 33 months) and PSA response rate (295 vs 65) Secondary analyses focused on the impact of abiraterone on symp-toms due to bone metastases [20] Although there was little difference in skeletal-related events in either study arm patients in the abiraterone arm had a statistically significant increase in time to development of the first skeletal-related event (25 vs 20 months) Common side effects of abiraterone compared with placebo included fluid retention (33 vs 24) and hypokalemia (18 vs 9) Nonspecific cardiac abnormalities (16 vs 12) abnormal liver function tests (11 vs 9) and hypertension (11 vs 8) also appeared to be more common in patients treated with abiraterone [1819]

Recent data from a second Phase III study of abiraterone also demonstrate delayed disease

Table 1 New and emerging hormonal therapies for the treatment of metastatic castration-resistant prostate cancer

Agent Therapeutic target

Stage of development and supporting data

Common side effects Ref

Abiraterone CYP17 (secondary androgen production)

Approved by the US FDA for the treatment of mCRPCImproved median OS in mCRPC after chemotherapy (148 vs 109 months HR 065 p lt 0001)Improved TTP prior to chemotherapy (165 vs 83 months HR 053 p lt 0001)

Fluid retention hypokalemia nonspecific cardiac abnormalities abnormal liver function tests hot flashes and hypertension

[1819101]

Enzalutamide Androgen receptor

Approved by the FDA for the treatment mCRPC postchemotherapyAfter chemotherapy improved median OS 184 vs 136 months (HR 063 p lt 0001)Awaiting final data in Phase III study prechemotherapy

Fatigue diarrhea hot flashes and mild musculoskeletal pain

[26]

TAK-700 CYP17 inhibitor In Phase III trials in mCRPC23 out of 39 patients had a PSA decline of ge90

Fatigue diarrhea and hypertension reported in early studies

[28]

ARN-509 Androgen receptor

In Phase III testing in mCRPC Fatigue nausea and pain reported in early studies

[106]

HR Hazard ratio mCRPC Metastatic castration-resistant prostate cancer OS Overall survival TTP Time-to-progression

Review Madan amp Arlen

wwwfuturemedicinecom 1135future science group

progression and improved OS in men with CRPC who have not received prior chemother-apy [21] In this study 1088 men with asymp-tomatic or minimally symptomatic mCRPC were randomly assigned to abiraterone plus prednisone or placebo plus prednisone The primary end points of this study were OS and radiographic progression-free survival The results show that median OS has not been reached in the abiraterone arm compared with 272 months in the placebo arm (hazard ratio [HR] 075 p = 001) In addition median radiographic time-to-progression (TTP) favored the abiraterone arm at 165 months compared with 83 months in the placebo arm (HR 053 p lt 0001) The FDA has approved abiraterone for use in this population based on this data [101]

EnzalutamideEnzalutamide an orally administered agent acts at multiple sites in the AR signaling pathway including blocking the binding of androgen to the AR In addition to binding to the AR with greater affinity than standard ARAs enzalu-tamide prevents downstream effects including nuclear translocation DNA binding and signal-ing to coactivators [22] Unlike first-generation ARAs which demonstrated agonist properties in approximately 15ndash20 of patients [2324] enzalu-tamide does not produce this negative effect Furthermore unlike abiraterone enzalutamide does not require the addition of daily steroids Initial studies with enzalutamide demonstrated significant activity in men with CRPC [25]

The AFFIRM trial a pivotal Phase III study of enzalutamide randomized 1199 patients with mCRPC the majority of whom had received numerous prior hormonal- and docetaxel-based chemotherapy regimens Concurrent therapy with steroids was permitted but not required on both treatment arms Patients were random-ized 21 to receive either a single daily dose of 160-mg enzalutamide or placebo [26] Patients randomized to the placebo arm were allowed to receive enzalutamide at time of progression The study demonstrated significantly increased OS in the enzalutamide arm compared with placebo (184 vs 136 months) Over half of patients randomized to receive enzalutamide had a gt50 decline in serum PSA levels Other clinical benefits in the enzalutamide arm con-sisted of fewer soft tissue lesions prolonged PSA progression and prolonged time to first skeletal-related events Toxicities were relatively minor however seven patients in the enzalutamide

arm had new onset of seizures compared with none in the placebo arm Based on these data the FDA-approved enzalutamide for mCRPC after docetaxel therapy in August 2012 [102]

As with older ARAs enzalutamide will prob-ably be used to treat early-stage prostate can-cer The minimal side effects of enzalutamide in patients with advanced disease will make it an attractive option for chemotherapy-naive mCRPC and even non-metastatic disease supplanting the use of older ARAs such as bicalutamide which are commonly used in non-metastatic disease [27] A second Phase III trial (PREVAIL) comparing enzalutamide with placebo in chemotherapy-naive patients with asymptomatic or minimally symptomatic mCRPC has completed accrual and is awaiting final data ana lysis [103]

TAK-700Other agents that inhibit CYP17 are in clini-cal trials the most advanced of which is a study of TAK-700 (orteronel) a selective oral 1720 lyase inhibitor TAK-700 is currently being compared with a placebo in two multi-center Phase III trials in chemotherapy-naive patients and patients who have progressed on docetaxel [104105] In a recent Phase II study (n = 39) TAK-700 was administered without prednisone in patients with non-metastatic CRPC and rising PSA levels a stage of prostate cancer for which there is no standard treat-ment To be able to treat these patients at high risk for metastases and death from their dis-ease with an effective therapy that does not require additional steroids would be a signifi-cant advance The primary objective of this Phase II study was to determine the percentage of patients who achieved a PSA reduction to le02 ngml Secondary objectives included the safety profile of TAK-700 PSA response rates time to PSA progression time to metastasis and duration of progression-free survival Results of this study were presented at the 2012 ASCO Annual Meeting Twelve patients achieved a PSA level of le02 ngml as their best response 23 had a decline in PSA of ge90 as their best response and median time to PSA progres-sion was 9 months The most common adverse events were fatigue (62) diarrhea (38) and hypertension (38) [28]

ARN-509ARN-509 is an ARA with a mechanism of action similar to enzalutamide It is a novel second-generation ARA targeted to treat CRPC where

Recent advances revolutionize treatment of metastatic prostate cancer Review


first-generation ARAs have failed ARN-509 was discovered through a screening for compounds with anti-androgenic activity in CRPC using prostate cancer cells rendered castration-resistant via AR overexpression The screen developed by Sawyers and Jung yielded ARN-509 which ini-tially demonstrated strong anti-tumor activity in mouse models of CRPC [27] ARN-509 inhibits both AR nuclear translocation and AR binding to androgen response elements in DNA [29] In contrast to the first-generation anti-androgen bicalutamide it exhibits no agonist activity in prostate cancer cells that overexpress AR Its oral bioavailability and long half-life allow for once-daily oral dosing In addition it has an excellent preclinical safety profile that makes it a candidate for either a single or combination therapy in various prostate cancer disease states ARN-509 is currently in the Phase II portion of a Phase III clinical trial being conducted at Memorial SloanndashKettering Cancer Center (NY USA) and various other institutions across the USA The open-label study will determine ARN-509rsquos anti-tumor activity safety and tolerability in patients with advanced CRPC [106]

ImmunotherapyImmunotherapy represents an alternative approach to treating prostate cancer (Table 2) Unlike targeted hormonal therapy and cyto-toxic chemotherapy that directly kill cancer cells immunotherapy targets the immune system The goal of all immunotherapies is to activate immune cells to target and kill cancer

cells Strategies for achieving this goal are as dis-parate as the characteristics of various immu-notherapeutic agents Since the tumor is not directly targeted by the treatment and immune activation is required the potential impact of immunotherapy is likely to be delayed relative to cytoreductive therapies [30] For this reason prudence dictates that immunotherapy be inves-tigated or employed early in the disease process so that patients have time to benefit from its potential albeit delayed benefits The attendant side effects of immunotherapy are also quite dif-ferent from those of cytotoxic agents Immune checkpoint inhibitors have been associated with autoimmune adverse events while therapeutic cancer vaccines have a negligible toxicity pro-file that primarily consists of local injection-site reactions or transient fevers

There are several reasons for immunothera-pyrsquos potential efficacy in prostate cancer First and foremost prostate cancerrsquos indolent disease course allows patients with metastatic disease to survive many years beyond the detection of radiographic metastasis [31] This markedly pro-longed disease course relative to more aggressive tumors such as lung or pancreatic cancer poten-tially allows for immunotherapy to generate an immune response that could ultimately yield clinical benefit In addition multiple tumor-associated antigens (TAAs) rarely expressed else-where in the body are overexpressed on prostate cancer cells [32ndash34] Studies have shown that the TAAs PSA PAP and prostate-specific membrane antigen are targeted in a minority of patients

Table 2 New and emerging immunotherapies for the treatment of metastatic castration-resistant prostate cancer

Agent Mechanism of immune activation



Sipuleucel-T A therapeutic cancer vaccine that is developed from each individual patientrsquos immune cells

Approved by the US FDA for the treatment of mCRPCImproved median OS in mCRPC (258 vs 217 months HR 077 p = 002)No change in TTP

Chills fatigue nausea arthralgia fever and anorexia

[42]

Prostvac An off-the-shelf therapeutic cancer vaccine that aims to activate immune cells in vivo

In Phase III trials in mCRPCImproved median OS in a Phase II study in mCRPC (251 vs 166 months HR 056 p = 00061)No change in TTP

Injection-site reactions fatigue fever chills edema and arthralgia

[43]

Ipilimumab An immune checkpoint inhibitor that enhances T-cell activity by limiting immune autoregulation

In Phase III trials in mCRPC approved for the treatment of metastatic melanomaImproved median OS in metastatic melanoma of approximately 10 months compared with 64 monthsNo change in TTP in metastatic melanoma

Diarrhea nausea fatigue anorexia emesis and immune-related toxicities including rash colitis and endocrine-related autoimmunity (based on the study in metastatic melanoma)

[49]




with prostate cancer prior to immunotherapy [35] The fact that these TAAs are focally expressed on malignant cells may enable the potential anti-tumor effects of immunotherapy Another dis-tinctive characteristic of prostate cancer is that myelosuppressive chemotherapy regimens are not indicated for prostate cancer unless a patient has aggressive disease that is either symptomatic andor rapidly progressing Although the true impact of chemotherapy can be immunostimu-latory as has been demonstrated with docetaxel it is possible that multiple myelosuppressive regi-mens can impair the immune systemrsquos ability to respond to immunotherapy [36] The absence of such treatment in early-stage prostate cancer may preserve the immune systemrsquos potential to be effectively activated by immunotherapy

Sipuleucel-TSipuleucel-T is a therapeutic cancer vaccine approved by the FDA for the treatment of asymptomatic mCRPC The vaccine is gener-ated from an individual patientrsquos own periph-eral immune cells collected via apheresis [3738] Once collected these immune cells are shipped to a central processing center where they are exposed to a fusion peptide consisting of PAP and granulocyte macrophage-colony stimulating factor (GM-CSF) PAP is the target antigen that immune cells will use to identify cancer cells beginning a process that will potentially end in immune-mediated cell lysis GM-CSF serves as an immune adjuvant to enhance immune activa-tion The patientrsquos immune cells are exposed to this PAPGM-CSF construct for approximately 48 h during ex vivo processing The immune cells are then shipped back to an infusion facil-ity where they are administered intravenously to the patient A full course of sipuleucel-T vaccine consists of three separate apheresis col-lectionex vivo processingreinfusion cycles performed every 2 weeks

Early clinical trials of sipuleucel-T demon-strated the safety of this form of therapy with no increased risk of autoimmunity [39] The most common adverse reactions were transient fever and flu-like symptoms Two small Phase III tri-als then evaluated the ability of sipuleucel-T to treat minimally symptomatic mCRPC [4041] The first of these trials failed to meet the pri-mary end point conventionally established as TTP resulting in the premature discontinuation of the second small Phase III trial Ultimately the initial Phase III trial demonstrated a survival advantage for patients treated with sipuleucel-T relative to the placebo but since this was a

secondary end point it was not sufficient to lead to FDA approval [40]

Subsequently a second larger Phase III trial with OS as the end point definitively addressed the clinical benefit of sipuleucel-T in mCRPC [42] The IMPACT trial enrolled 512 patients with minimally symptomatic mCRPC random-izing them 21 in favor of sipuleucel-T relative to the placebo As with previous studies there was no significant difference in TTP based on objec-tive parameters (37 months in the sipuleucel-T arm vs 36 months in the placebo arm HR 095 p = 063) The findings for OS however did show a significant advantage for patients treated with sipuleucel-T Median OS was 258 versus 217 months in favor of patients treated with sipuleucel-T with a 3-year survival proba-bility of 317 versus 230 (HR 077 p = 002) Based on these findings the FDA approved sip-uleucel-T for the treatment of minimally symp-tomatic mCRPC ushering in a modern age of immunotherapy for the treatment of cancer [107]

ProstvacTwo other forms of immunotherapy are cur-rently being evaluated in Phase III trials PSA-TRICOM (Prostvacreg Bavarian Nordic Inc Kvistgaard Denmark) an alternative vaccine strategy to sipuleucel-T is composed of modi-fied poxviruses that activate immune cells in vivo and therefore does not require apheresis or off-site cellular processing [43] This off-the-shelf vaccine is injected subcutaneously with the goal of delivering targeting information to immune cells activating them to target and lyze prostate cancer cells Early clinical trials with Prostvac have demonstrated that it is well tolerated with fever flu-like symptoms and injection-site reac-tions the most common toxicities Phase II tri-als have also demonstrated that the vaccine can enhance the ability of T cells to target PSA on prostate cancer cells and improve survival [4445] A Phase III study is being conducted interna-tionally in minimally symptomatic chemo-therapy-naive mCRPC patients and results are anticipated in 2016 [108]

IpilimumabAnother form of immunotherapy augments immune response by interfering with T-cell regulation Within 24ndash48 h after activation T cells express CTLA-4 This moleculersquos inter-action with antigen-presenting cells has a mod-erating effect on T cells [46] The importance of this molecule is demonstrated in CTLA-4-knockout mice who rapidly succumb to T-cell



hyperactivity which leads to T-cell infiltration and destruction of vital organs [47] Ipilimumab is a monoclonal antibody that blocks the inter-action between antigen-presenting cells and the CTLA-4 molecule on T cells preventing T-cell regulation with the goal of having the consti-tutively activated T cells attack cancer cells [48] Ipilimumab has demonstrated improved survival in metastatic melanoma [49] However unlike vaccines it is associated with autoimmune side effects such as rash colitis and autoimmune endocrinopathies

Two Phase III trials are evaluating ipilimumab in mCRPC The first in chemotherapy-naive patients will compare ipilimumab versus pla-cebo [109] The second in patients with mCRPC who have been treated with chemotherapy will use isolated external-beam radiation on a minor-ity of bone lesions to potentially enhance the immune response [110] This strategy is based on preclinical data and the clinical phenom-enon of the abscopal effect all of which suggest that radiation can potentiate and enhance an immune response [5051] To fully explore this hypothesis patients will receive either ipilim-umab or placebo postradiation The primary end point of each of these trials is OS [109110]

The sipuleucel-T dilemmaAny new form of therapy raises a host of new issues for clinicians and patients While the limited toxicity profile of sipuleucel-T makes it very attractive to patients and their oncologists the clinical dilemma created by sipuleucel-T is unique to this class of emerging immuno-therapies [52] How can physicians determine if sipuleucel-T is working in a given patient if it does not lead to short-term improvement in disease progression as demonstrated in mul-tiple Phase III trials Furthermore patients may become concerned since their PSA level is likely to continue to rise after therapy Although some associations between immunologic response and clinical outcome have been presented they fall short of the criteria required for use as surrogate biomarkers [53] Indeed the complexity of the immune response which is perhaps its greatest strength may prevent a simple assay from iden-tifying responders from nonresponders Varia-tions in patientsrsquo immune responses to therapy may further limit the development of a univer-sal biomarker as an indicator of future clinical benefit These complex questions are new to medical oncologists accustomed to dealing with standard therapies where long-term benefits can be expected only when short-term benefits

are measurable Furthermore this dilemma has quelled some of the enthusiasm for sipuleucel-T in common clinical practice and has even given rise to specious suggestions that sipuleucel-T trials were somehow significantly flawed in their design and data ana lysis although more practical scientific considerations do not sup-port these allegations [54ndash57] It is more prob-able that a new form of therapy that differs mechanistically such as sipuleucel-T needs to be perceived and evaluated differently to conventional cytotoxic agents Emerging data from multiple clinical trials suggest that mod-ern immunotherapies may affect tumor growth differently to cytotoxic therapies as evidenced by results of the previously described trials of ipilimumab and PSA-TRICOM where these agents also improved OS without changing short-term progression [4449]

One hypothesis that could explain the phe-nomenon of improved OS without a change in TTP (which may be characteristic of cancer vac-cine therapy and not unique to sipuleucel-T) is that over time the effects of immunotherapy slow tumor growth without causing a short-term decrease in tumor volume [5859] This hypothesis is supported by retrospective analyses of multiple vaccine trials in prostate cancer by which PSA level seems to be rising at a significantly slower rate after treatment with vaccine [6061] Although PSA should not be used as the sole indicator for discontinuing therapy it may signal the manner in which immunotherapy is affecting the tumor Ultimately prospective trials will be required to evaluate this hypothesis and clinical outcomes will need to be associated with changes in PSAtumor growth rates In the meantime cli-nicians should consider sipuleucel-T for patients with minimal symptoms but should not wait for evidence of clinical response to sipuleucel-T to initiate subsequent therapies [52]

Other emerging therapiesAlpharadinreg

Additional treatment strategies are also in development for the treatment of mCRPC (Table 3) Radiopharmaceuticals have been used clinically for some time Strontium-89 and samarium-153 have been used as palliative treat-ments for patients with bone metastases while ibritumomab tiuxetan (Zevalinreg Spectrum Pharmaceuticals CA USA) a radiotherapeu-tic antibody has demonstrated clinical efficacy in lymphomas [62ndash64] Radium-223 (Alpha-radinreg Algeta Oslo Norway) is an a-radia-tion-emitting agent which differentiates it from



strontium-89 and samarium-153 which emit g- and b-particles The significance of this is that a-particles carry higher radioactive energy but travel shorter distances (lt100 microm) allow-ing for greater potential lethality to cancer cells but less toxicity to normal tissue beyond the tumor microenvironment Perhaps most significant is that unlike samarium-153 and strontium-89 there is less myelosuppression with radium-223 [65]

A recent Phase III study evaluated radium-223 and best supportive care compared with placebo and best supportive care in men with mCRPC at least two bone metastases and no visceral disease [66] The study which included both docetaxel-treated and -naive patients random-ized 922 men 21 in favor of radium-223 and was designed with OS as its primary end point The results indicated improved survival for patients treated with radium-223 with a median OS of 14 versus 112 months for placebo (HR 0695 p = 000185) Furthermore in patients treated with radium-223 the time to first skeletal-related morbidity was significantly delayed (median 136 vs 84 months HR 0610 p = 000046) It is anticipated that these findings will be suf-ficient to lead to FDA approval giving oncolo-gists a radiopharmaceutical with palliative prop-erties less myelosuppression and the possibility of improved survival

CabozantinibCabozantinib is a promising dual tyrosine kinase inhibitor that targets both the mesenchy-malndashepithelial transition and VEGFR2 both of which are implicated in the progression of pros-tate cancer [6768] Previous tyrosine kinase and VEGF inhibitors have failed to enhance clinical outcomes in mCRPC but striking findings in early-phase trials of cabozantinib have drawn significant attention [469]

In a randomized discontinuation study 171 patients with mCRPC were initially treated for 3 months with cabozantinib then randomized to continue the drug or receive a

placebo Median progression-free survival for the 31 patients randomized after 3 months was 239 weeks for those on cabozantinib compared with 59 weeks for those on placebo [70] Even more noteworthy was the objective response rate after 3 months among all patients treated 75 had stable disease and 5 had responses while 72 had regression of soft tissue lesions and 68 had improvements on bone scan Improve-ments on bone scan are rarely seen with other treatments for mCRPC and certainly not on this scale The apparent improvements in bone metastasis were accompanied by improve-ments in pain symptoms in 67 of patients and improvement in serum markers associ-ated with bone lesions (alkaline phosphatase and c-telopeptide) These associations between serum marker changes and symptom improve-ment suggest that the impact of cabozantinib on the bonetumor microenvironment is genuine and not just an artefact of the drugrsquos impact on imaging studies

Based on these promising results the study was discontinued early so that additional studies could be initiated Fatigue decreased appetite and a spectrum of gastrointestinal symptoms (nausea diarrhea and constipation) were seen in more than half of the patients For this rea-son a recent study evaluated cabozantinib at a lower dose (40 mg compared with 100 mg in the discontinuation study) and found that the drug was better tolerated with similar clinical effect [71] Based on these findings a Phase III study has been launched in mCRPC patients who have received docetaxel comparing cabozantinib to mitoxantrone and prednisone [111]

These emerging data of cabozantonibrsquos poten-tial anti-tumor effects in bone lesions combined with potential therapeutic and palliative effects of Alpharadin are of great potential clinical importance Together with previous data that suggest the rank-ligand inhibitor denosumab may delay bone metastasis there may finally be meaningful progress in addressing the pri-mary metastatic site for most prostate cancer

Table 3 Other noteworthy emerging therapies for the treatment of metastatic castration-resistant prostate cancer

Agent Description Stage of development Ref

Alpharadinreg A radiopharmaceutical based on a-particles that targets metastatic lesions in bones

Demonstrated improved OS in Phase III trials in mCRPC pending US FDA evaluation

[66]

Cabozantinib A tyrosine kinase inhibitor that targets both MET and VEGFR2 In Phase III trials in mCRPC [111]

Tasquinimod A quinolone-3-carbozamide with both antiangiogenic and immunologic properties

In Phase III trials in mCRPC [112]

mCRPC Metastatic castration-resistant prostate cancer OS Overall survival



patients [72] A better understanding of the bone (tumor) microenvironment may have palliative effects in the short term but could limit meta-static disease in the long term if the underlying mechanisms that promote bone metastasis are better understood

TasquinimodTasquinimod is another emerging agent with antiangiogenic properties This treatment is a quinolone-3-carbozamide that has previously demonstrated preclinical evidence of anti-tumor activity in prostate cancer [7374] It has been shown to decrease angiogenesis perhaps through the inhibition of genes that can be induced by hypoxia Furthermore it has been found to be a potent inhibitor of S1900A9 which is expressed in the tumor microenvironment and on myeloid-derived suppressor cells which have been impli-cated in immune suppression [75] Suppression of immune responses may be important since it creates a more permissive environment for tumor growth [76]

Phase I studies of tasquinimod enrolled 32 chemotherapy-naive CRPC patients The most common adverse events included inflam-mation nausea and fatigue Rare but serious adverse events included sinus tachycardia cere-bral infarction and hyperamylasemia [77] A sub-sequent randomized Phase II trial randomized 134 minimally symptomatic mCRPC patients 21 to tasquinimod or placebo Although there were no significant changes in PSA progression in the two arms of the trial clinical (pain) or radiographic progression-free survival favored the tasquinimod arm (76 vs 33 months p = 00042) [78] Currently a Phase III study of tasquinimod versus placebo is enrolling mCRPC patients in order to determine its true efficacy in mCRPC [112]

ConclusionAlthough the development of docetaxel raised hopes for rapid progress in the treatment of mCRPC nearly a decade had passed before new advances in mCRPC therapy came to fruition The rediscovery of the importance of the AR and the focus on secondary androgen production has led to the development of modern hormonal therapies that appear to be significant improve-ments over their predecessors Abiraterone is now approved for use in all mCRPC patients not just those who have had prior chemotherapy and approval of enzalutamide will probably follow pending final results from studies in mCRPC chemotherapy-naive patients

Many studies evaluating these new hormonal agents in non-metastatic and newly diagnosed prostate cancer patients are already underway The tolerability of enzalutamide is certainly an attractive benefit for patients with asymp-tomatic and non-metastatic disease Additional studies using CYP17 lyase inhibitors (including abiraterone) with limited or no use of predni-sone would also be appropriate for patients in this population Long-term steroid exposure is a concern for non-metastatic patients who may have survival rates reaching 5ndash10 years with their disease Limiting supplemental steroids in this population is therefore desirable These tri-als could determine the clinical impact of new hormonal therapies and whether their impact is more appreciated by their use earlier in the disease course Meanwhile there are significant advances in the development of next-generation ARAs and agents that can suppress secondary androgen production

The impact of immunotherapy in mCRPC should not come as a complete surprise In retrospect prostate cancerrsquos indolent disease course and the numerous tumor antigens iden-tified make prostate cancer an ideal target for immunotherapy Although sipuleucel-T has been FDA approved for several years clini-cians need to become more familiar with how to use this new therapy in order to maximize its potential clinical benefit This need becomes urgent when one considers that both Prostvac and ipilimumab are being utilized in ongoing Phase III trials in mCRPC that could lead to further immunotherapeutic options in the next several years Furthermore the negligible toxic-ity profile of therapeutic cancer vaccines the ability of hormonal therapies and radiation to enhance immune responses and the potential to induce long-lasting immunologic effects have led to immunotherapy trials in earlier stages of prostate cancer with the goal of augmenting the clinical impact seen in late-stage disease These trials could establish the future utility of immunotherapy in adjuvant disease and non-metastatic prostate cancer in addition to mCRPC

Future perspectiveWith the abundance of new therapies available in the treatment of prostate cancer come prac-tical dilemmas regarding cost It is important to note that the high price of these new thera-pies may not be sustainable given the growing economic concerns of healthcare and there is no clear mechanism by which these issues can



be addressed in clinical development This is a problem not just limited to oncology and it is probably an issue that cannot be ignored as these and other agents emerge in the treatment of prostate cancer

Nonetheless the rapid emergence of therapies in the last few years has led to questions of how they can best be deployed in clinical practice Current and future trials will also investigate how best to sequence these new hormonal agents immunotherapies radiopharmaceuticals and targeted molecular therapies and whether they are more effective when used in combina-tion or sequentially The responsibilities that come with multiple new therapies are a wel-come dilemma for clinicians who just a few years ago had limited options for their patients with mCRPC In spite of these novel agents it should be clear that the judicious use of chemotherapy

in more advanced and symptomatic mCRPC will still have a very important palliative and therapeutic role as we move into this new age of therapy In recent years great strides have been made in treatments for mCRPC Applying this knowledge in the non-metastatic and adjuvant settings to enhance the cure rate for prostate cancer should be the ultimate goal

Executive summary

Modern hormonal therapiesn Modern hormonal therapies such as enzalutamide and abiraterone have validated the androgen receptor and secondary androgen

production as crucial targets in metastatic castration-resistant prostate cancer (mCRPC) These agents are now US FDA approved based on improvements in overall survival and have resulted in delaying the need for chemotherapy in many patients

n Additional agents targeting the androgen receptor or limiting secondary androgen production via CYP17 inhibition are in development aiming to improve on both enzalutamide and abiraterone

Immune-stimulating therapiesn Immunotherapy works by a different mechanism to standard therapies having delayed but sustained effects and improving survival

Sipuleucel-T should be considered in mCRPC where pace of disease is slow tumor burden is low and symptoms are minimaln An off-the-shelf vaccine (Prostvacreg Bavarian Nordic Inc Kvistgaard Denmark) and an immune checkpoint inhibitor approved in

metastatic melanoma (ipilimumab) are in Phase III testing in mCRPC and may provide additional immunotherapy options

Emerging therapies in prostate cancern The radiopharmaceutical Alpharadinreg (Algeta Oslo Norway) has demonstrated the ability to improve survival along with palliative

impact and is being considered for FDA approval n Cabozantinib is a tyrosine kinase inhibitor that targets both MET and VEGFR2 and has had a remarkable impact on bone lesions in

mCRPC This agent is currently in a Phase III trial in mCRPCn Tasquinimod is an agent with both antiangiogenic and immunologic properties that has demonstrated preliminary efficacy in prostate

cancer and is currently in Phase III testingn Future clinical trials will evaluate the optimal sequencecombination of therapies in mCRPC and determine if any of these new agents

can be used earlier in the disease process including in the adjuvant setting in order to improve the ability to cure prostate cancer

Financial amp competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the sub-ject matter or materials discussed in the manuscript This includes employment consultancies honoraria stock ownership or options expert testimony grants or patents received or pending or royalties

No writing assistance was utilized in the production of this manuscript

ReferencesPapers of special note have been highlighted asn of interestnn of considerable interest

1 Tannock IF de Wit R Berry WR et al Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer N Engl J Med 351(15) 1502ndash1512 (2004)

2 Petrylak DP Tangen CM Hussain MH et al Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer N Engl J Med 351(15) 1513ndash1520 (2004)

3 Nelson JB Fizazi K Miller K et al Phase 3 randomized placebo-controlled study of zibotentan (ZD4054) in patients with castration-resistant prostate cancer metastatic to bone Cancer 118(22) 5709ndash5718 (2012)

4 Kelly WK Halabi S Carducci M et al Randomized double-blind placebo-controlled Phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer CALGB 90401 J Clin Oncol 30(13) 1534ndash1540 (2012)

5 Scher HI Jia X Chi K et al Randomized open-label Phase III trial of docetaxel plus

high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer J Clin Oncol 29(16) 2191ndash2198 (2011)

6 Aragon-Ching JB Jain L Gulley JL et al Final analysis of a Phase II trial using sorafenib for metastatic castration-resistant prostate cancer BJU Int 103(12) 1636ndash1640 (2009)

7 Tannock I Fizazi K Ivanov S et al Aflibercept versus placebo in combination with docetaxelprednisone for first-line treatment of men with metastatic castration-resistant prostate cancer (mCRPC) results



from the multinational Phase III trial (VENICE) J Clin Oncol 31(Suppl 6) Abstract 13 (2013)

8 Araujo JC Trudel GC Saad F et al Overall survival (OS) and safety of dasatinibdocetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC) results from the randomized Phase III READY trial J Clin Oncol 31(Suppl 6) Abstract LBA8 (2013)

9 Michaelson MD Oudard S Ou Y et al Randomized placebo-controlled Phase III trial of sunitinib in combination with prednisone (SU+P) versus prednisone (P) alone in men with progressive metastatic castration-resistant prostate cancer (mCRPC) J Clin Oncol 29(Suppl) Abstract 4515 (2011)

10 De Bono JS Oudard S Ozguroglu M et al Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 376(9747) 1147ndash1154 (2010)

n Clinical trial that established the first therapy for metastatic castration-resistant prostate cancer (mCRPC) after treatment with docetaxel

11 Siegel R Naishadham D Jemal A Cancer statistics 2012 CA Cancer J Clin 62(1) 10ndash29 (2012)

12 Huggins C Hodges CV Studies on prostatic cancer I The effect of castration of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate CA Cancer J Clin 22(4) 232ndash240 (1972)

13 Kojima S Suzuki H Akakura K Shimbo M Ichikawa T Ito H Alternative antiandrogens to treat prostate cancer relapse after initial hormone therapy J Urol 171(2 Pt 1) 679ndash683 (2004)

14 Kassouf W Tanguay S Aprikian AG Nilutamide as second line hormone therapy for prostate cancer after androgen ablation fails J Urol 169(5) 1742ndash1744 (2003)

15 Scher HI Liebertz C Kelly WK et al Bicalutamide for advanced prostate cancer the natural versus treated history of disease J Clin Oncol 15(8) 2928ndash2938 (1997)

16 Ryan CJ Smith MR Fong L et al Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy J Clin Oncol 28(9) 1481ndash1488 (2010)

17 Madan RA Arlen PM Abiraterone Cougar biotechnology IDrugs 9(1) 49ndash55 (2006)

18 De Bono JS Logothetis CJ Molina A et al Abiraterone and increased survival in

metastatic prostate cancer N Engl J Med 364(21) 1995ndash2005 (2011)

nn First clinical trial that established a clear role for anti-androgens in mCRPC

19 Fizazi K Scher HI Molina A et al Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer final overall survival analysis of the COU-AA-301 randomised double-blind placebo-controlled Phase 3 study Lancet Oncol 13(10) 983ndash992 (2012)

20 Logothetis CJ Basch E Molina A et al Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer exploratory analysis of data from the COU-AA-301 randomised trial Lancet Oncol 13(12) 1210ndash1217 (2012)

21 Ryan CJ Smith MR De Bono JS et al Abiraterone in metastatic prostate cancer without previous chemotherapy N Engl J Med 368(2) 138ndash148 (2013)

n Provides clinical evidence that abiraterone can improve survival in chemotherapy-naive mCRPC

22 Chen Y Clegg NJ Scher HI Anti-androgens and androgen-depleting therapies in prostate cancer new agents for an established target Lancet Oncol 10(10) 981ndash991 (2009)

23 Sartor AO Tangen CM Hussain MH et al Antiandrogen withdrawal in castrate-refractory prostate cancer a Southwest Oncology Group trial (SWOG 9426) Cancer 112(11) 2393ndash2400 (2008)

24 Small EJ Halabi S Dawson NA et al Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients a Phase III trial (CALGB 9583) J Clin Oncol 22(6) 1025ndash1033 (2004)

25 Scher HI Beer TM Higano CS et al Antitumour activity of MDV3100 in castration-resistant prostate cancer a Phase 1ndash2 study Lancet 375(9724) 1437ndash1446 (2010)

26 Scher HI Fizazi K Saad F et al Increased survival with enzalutamide in prostate cancer after chemotherapy N Engl J Med 367(13) 1187ndash1197 (2012)

nn Established enzalutamide as a treatment for mCRPC patients who have already had docetaxel

27 Sharifi N Dahut WL Steinberg SM et al A retrospective study of the time to clinical endpoints for advanced prostate cancer BJU Int 96(7) 985ndash989 (2005)

28 George DJ Corn PG Michaelson MD Hammers HJ Alumkal J Safety and activity of the investigational agent orteronel (ortl)

without prednisone in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) and rising prostate-specific antigen (PSA) updated results of a Phase II study J Clin Oncol 30(Suppl) Abstract 4549 (2012)

29 Clegg NJ Wongvipat J Joseph JD et al ARN-509 a novel antiandrogen for prostate cancer treatment Cancer Res 72(6) 1494ndash1503 (2012)

30 Madan RA Schwaab T Gulley JL Strategies for optimizing the clinical impact of immunotherapeutic agents such as sipuleucel-T in prostate cancer J Natl Compr Canc Netw 10(12) 1505ndash1512 (2012)

31 Pound CR Partin AW Eisenberger MA Chan DW Pearson JD Walsh PC Natural history of progression after PSA elevation following radical prostatectomy JAMA 281(17) 1591ndash1597 (1999)

32 Bostwick DG Pacelli A Blute M Roche P Murphy GP Prostate specific membrane antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma a study of 184 cases Cancer 82(11) 2256ndash2261 (1998)

33 Goldfarb DA Stein BS Shamszadeh M Petersen RO Age-related changes in tissue levels of prostatic acid phosphatase and prostate specific antigen J Urol 136(6) 1266ndash1269 (1986)

34 Wang MC Valenzuela LA Murphy GP Chu TM Purification of a human prostate specific antigen Invest Urol 17(2) 159ndash163 (1979)

35 Chakraborty NG Stevens RL Mehrotra S et al Recognition of PSA-derived peptide antigens by T cells from prostate cancer patients without any prior stimulation Cancer Immunol Immunother 52(8) 497ndash505 (2003)

36 Garnett CT Schlom J Hodge JW Combination of docetaxel and recombinant vaccine enhances T-cell responses and antitumor activity effects of docetaxel on immune enhancement Clin Cancer Res 14(11) 3536ndash3544 (2008)

37 Patel PH Kockler DR Sipuleucel-T a vaccine for metastatic asymptomatic androgen-independent prostate cancer Ann Pharmacother 42(1) 91ndash98 (2008)

38 Rini BI Technology evaluation APC-8015 dendreon Curr Opin Mol Ther 4(1) 76ndash79 (2002)

39 Small EJ Fratesi P Reese DM et al Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells J Clin Oncol 18(23) 3894ndash3903 (2000)

40 Small EJ Schellhammer PF Higano CS et al Placebo-controlled Phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic asymptomatic hormone refractory prostate



cancer J Clin Oncol 24(19) 3089ndash3094 (2006)

41 Higano CS Schellhammer PF Small EJ et al Integrated data from 2 randomized double-blind placebo-controlled Phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer Cancer 115(16) 3670ndash3679 (2009)

42 Kantoff PW Higano CS Shore ND et al Sipuleucel-T immunotherapy for castration-resistant prostate cancer N Engl J Med 363(5) 411ndash422 (2010)

nn Demonstrates the efficacy (improved survival) of a therapuetic cancer vaccine in prostate cancer

43 Madan RA Arlen PM Mohebtash M Hodge JW Gulley JL Prostvac-VF a vector-based vaccine targeting PSA in prostate cancer Expert Opin Invest Drugs 18(7) 1001ndash1011 (2009)

44 Kantoff PW Schuetz TJ Blumenstein BA et al Overall survival analysis of a Phase II randomized controlled trial of a poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer J Clin Oncol 28(7) 1099ndash1105 (2010)

n Suggests the efficacy of an off-the-shelf therapeutic cancer vaccine

45 Gulley JL Arlen PM Madan RA et al Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer Cancer Immunol Immunother 59(5) 663ndash674 (2010)

46 Krummel MF Allison JP CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation J Exp Med 182(2) 459ndash465 (1995)

47 Waterhouse P Penninger JM Timms E et al Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4 Science 270(5238) 985ndash988 (1995)

48 Pardoll D Releasing the brakes on antitumor immune response Science 271(5256) 1691 (1996)

49 Hodi FS OrsquoDay SJ Mcdermott DF et al Improved survival with ipilimumab in patients with metastatic melanoma N Engl J Med 363(8) 711ndash723 (2010)

50 Chakraborty M Abrams SI Camphausen K et al Irradiation of tumor cells up-regulates Fas and enhances CTL lytic activity and CTL adoptive immunotherapy J Immunol 170(12) 6338ndash6347 (2003)

51 Postow MA Callahan MK Barker CA et al Immunologic correlates of the abscopal effect in a patient with melanoma N Engl J Med 366(10) 925ndash931 (2012)

52 Madan RA Gulley JL Fojo T Dahut WL Therapeutic cancer vaccines in prostate cancer the paradox of improved survival without changes in time to progression Oncologist 15(9) 969ndash975 (2010)

53 Sheikh NA Petrylak D Kantoff PW et al Sipuleucel-T immune parameters correlate with survival an analysis of the randomized Phase 3 clinical trials in men with castration-resistant prostate cancer Cancer Immunol Immunother 62(1) 137ndash147 (2013)

54 Huber ML Haynes L Parker C Iversen P Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer J Natl Cancer Inst 104(4) 273ndash279 (2012)

55 Kantoff PW Higano CS Small EJ Whitmore JB Frohlich MW Schellhammer PF Re interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer J Natl Cancer Inst 104(14) 1107ndash1109 author reply 1109ndash1112 (2012)

56 Gulley JL Leitman SF Dahut W Schlom J Re interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer J Natl Cancer Inst 104(14) 1106 author reply 1109ndash1112 (2012)

57 Drake CG Re interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer J Natl Cancer Inst 104(18) 1422 author reply 1422ndash1423 (2012)

58 Stein WD Gulley JL Schlom J et al Tumor regression and growth rates determined in five intramural NCI prostate cancer trials the growth rate constant as an indicator of therapeutic efficacy Clin Cancer Res 17(4) 907ndash917 (2011)

59 Madan RA Bilusic M Heery C Schlom J Gulley JL Clinical evaluation of TRICOM vector therapeutic cancer vaccines Semin Oncol 39(3) 296ndash304 (2012)

60 Dipaola RS Chen Y Bubley GJ et al A Phase II study of PROSTVAC-V (vaccinia)TRICOM and PROSTVAC-F (fowlpox)TRICOM with GM-CSF in patients with PSA progression after local therapy for prostate cancer results of ECOG 9802 Presented at 2009 Genitourinary Cancers Symposium Orlando FL USA 26ndash28 February 2009

61 Beer TM Bernstein GT Corman JM et al Randomized trial of autologous cellular immunotherapy with sipuleucel-T in androgen-dependent prostate cancer Clin Cancer Res 17(13) 4558ndash4567 (2011)

62 Sartor O Reid RH Hoskin PJ et al Samarium-153ndashLexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer Urology 63(5) 940ndash945 (2004)

63 Zorga P Birkenfeld B Listewnik MH Piwowarska-Bilska H Effectiveness of strontium-89 palliative therapy in patients with painful bone metastases Ann Acad Med Stetin 57(1) 49ndash53 discussion 53 (2011)

64 Witzig TE Gordon LI Cabanillas F et al Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade follicular or transformed B-cell non-Hodgkinrsquos lymphoma J Clin Oncol 20(10) 2453ndash2463 (2002)

65 Nilsson S Strang P Aksnes AK et al A randomized dose-response multicenter Phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer Eur J Cancer 48(5) 678ndash686 (2012)

66 Sartor AO Heinrich D Helle SI et al Radium-223 chloride impact on skeletal-related events in patients with castration-resistant prostate cancer (CRPC) with bone metastases a Phase III randomized trial (ALSYMPCA) J Clin Oncol 30(Suppl 5) Abstract 9 (2012)

n Phase III trial showing that radium-223 with best supportive care improves survival in mCRPC when compared with best supportive care alone

67 Pisters LL Troncoso P Zhau HE Li W Von Eschenbach AC Chung LW c-met proto-oncogene expression in benign and malignant human prostate tissues J Urol 154(1) 293ndash298 (1995)

68 Borre M Offersen BV Nerstrom B Overgaard J Microvessel density predicts survival in prostate cancer patients subjected to watchful waiting Br J Cancer 78(7) 940ndash944 (1998)

69 Michaelson MD Oudard S Ou Y Sengelov L Saad F Houede N Randomized placebo-controlled Phase III trial of sunitinib in combination with prednisone versus prednisone alone in men with progressive metastatic castration-resistant prostate cancer J Clin Oncol 29(Suppl) Abstract 4515 (2011)

70 Smith DC Smith MR Sweeney C et al Cabozantinib in patients with advanced prostate cancer results of a Phase II randomized discontinuation trial J Clin Oncol 31(4) 412ndash419 (2013)

71 Lee RJ Michaelson MD Saylor PJ Gurski CA Rothenberg SM Investigator-sponsored trial of efficacy and tolerability of cabozantinib at lower dose a dose-finding study in men with castration-resistant



prostate cancer and bone metastases J Clin Oncol 30(Suppl) Abstract 4566 (2012)

72 Smith MR Saad F Coleman R et al Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer results of a Phase 3 randomised placebo-controlled trial Lancet 379(9810) 39ndash46 (2012)

73 Dalrymple SL Becker RE Isaacs JT The quinoline-3-carboxamide anti-angiogenic agent tasquinimod enhances the anti-prostate cancer efficacy of androgen ablation and taxotere without effecting serum PSA directly in human xenografts Prostate 67(7) 790ndash797 (2007)

74 Isaacs JT Pili R Qian DZ et al Identification of ABR-215050 as lead second generation quinoline-3-carboxamide anti-angiogenic agent for the treatment of prostate cancer Prostate 66(16) 1768ndash1778 (2006)

75 Kallberg E Vogl T Liberg D et al S100A9 interaction with TLR4 promotes tumor growth PLoS One 7(3) e34207 (2012)

76 Murdoch C Muthana M Coffelt SB Lewis CE The role of myeloid cells in the promotion of tumour angiogenesis Nat Rev Cancer 8(8) 618ndash631 (2008)

77 Bratt O Haggman M Ahlgren G Nordle O Bjork A Damber JE Open-label clinical Phase I studies of tasquinimod in patients with castration-resistant prostate cancer Br J Cancer 101(8) 1233ndash1240 (2009)

78 Pili R Haggman M Stadler WM et al Phase II randomized double-blind placebo-controlled study of tasquinimod in men with minimally symptomatic metastatic castrate-resistant prostate cancer J Clin Oncol 29(30) 4022ndash4028 (2011)

Websites101 US FDA Abiraterone Acetate

wwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDER ucm253139htm

102 FDA Enzalutamide (XTANDI capsules) wwwfdagovDrugsInformationOnDrugsApprovedDrugsucm317997htm

103 ClinicalTrialsgov A Safety and Efficacy Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer (PREVAIL) httpclinicaltrialsgovshowNCT01212991

104 ClinicalTrialsgov Study Comparing Orteronel Plus Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer httpclinicaltrialsgovct2showNCT01193257

105 ClinicalTrialsgov Study Comparing Orteronel Plus Prednisone in Patients With Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer httpclinicaltrialsgovshowNCT01193244

106 ClinicalTrialsgov Safety Pharmacokinetic and Proof-of-Concept Study of ARN-509 in Castration-Resistant Prostate Cancer

httpclinicaltrialsgovct2showNCT01171898

107 FDA Approval Letter ndash Provenge wwwfdagovBiologicsBloodVaccinesCellularGene TherapyProductsApprovedProductsucm210215htm

108 ClinicalTrialsgov A Phase 3 Efficacy Study of a Recombinant Vaccinia Virus Vaccine to Treat Metastatic Prostate Cancer (Prospect) httpclinicaltrialsgovct2showNCT01322490

109 ClinicalTrialsgov Phase 3 Study of Immunotherapy to Treat Advanced Prostate Cancer httpclinicaltrials govct2showNCT01057810

110 ClinicalTrialsgov Study of Immunotherapy to Treat Advanced Prostate Cancer httpclinicaltrialsgovct2showNCT00861614

111 ClinicalTrialsgov Study of Cabozantinib (XL184) Versus Mitoxantrone Plus Prednisone in Men With Previously Treated Symptomatic Castration-resistant Prostate Cancer (COMET-2) httpclinicaltrialsgovct2showNCT01522443

112 ClinicalTrialsgov A Study of Tasquinimod in Men With Metastatic Castrate Resistant Prostate Cancer httpclinicaltrialsgovshowNCT01234311



also in the tumor These recent developments (Table 1) have led to the approval of the ARAs abiraterone and enzalutamide both of which have significantly improved overall survival (OS) compared with placebo in Phase III tri-als in patients with castration-resistant prostate cancer (CRPC)

AbirateroneAdministered orally abiraterone irreversibly inhibits the products of the CYP17 gene includ-ing both 1720 lyase and 17-a-hydroxylase [1617] Through this mechanism of action abiraterone blocks the synthesis of androgens in the tumor testes and adrenal glands The toxicity profile of abiraterone depends on the mechanism of action Inhibition of 17-a-hydroxylase can result in decreased cortisol levels and a compensatory rise in adrenocorticotropic hormone (ACTH) level which is mediated by a hypothalamic response to partial adrenal inhibition Increased release of ACTH can cause increased produc-tion of adrenal mineralocorticoid producing both hypertension and hypokalemia However when abiraterone is given without concomitant glucocorticoids patients typically do not experi-ence clinical adrenal insufficiency since cortisol production is preserved The effects of mineralo-corticoid excess can be attenuated by coadmin-istration of prednisone which reduces ACTH-mediated stimulation of the adrenal glands

The clinical benefit of abiraterone was first observed in a Phase III trial in men with mCRPC

who had received prior docetaxel [1819] In this study 1195 men were randomized 21 to receive either abiraterone at 1000 mgday with oral pred-nisone two-times 5 mgday or a placebo with prednisone as a control Treatment continued until disease progression The study was termi-nated when results of an interim ana lysis exceeded prespecified criteria The final ana lysis of OS was conducted at a median follow-up of 20 months There was an increase in OS for patients ran-domized to abiraterone (median 158 months) compared with patients in the placebo arm (median 112 months) Statistically significant improvements were also seen in time to PSA pro-gression (85 vs 66 months) radiologic progres-sion-free survival (56 vs 33 months) and PSA response rate (295 vs 65) Secondary analyses focused on the impact of abiraterone on symp-toms due to bone metastases [20] Although there was little difference in skeletal-related events in either study arm patients in the abiraterone arm had a statistically significant increase in time to development of the first skeletal-related event (25 vs 20 months) Common side effects of abiraterone compared with placebo included fluid retention (33 vs 24) and hypokalemia (18 vs 9) Nonspecific cardiac abnormalities (16 vs 12) abnormal liver function tests (11 vs 9) and hypertension (11 vs 8) also appeared to be more common in patients treated with abiraterone [1819]

Recent data from a second Phase III study of abiraterone also demonstrate delayed disease

Table 1 New and emerging hormonal therapies for the treatment of metastatic castration-resistant prostate cancer

Agent Therapeutic target



Abiraterone CYP17 (secondary androgen production)

Approved by the US FDA for the treatment of mCRPCImproved median OS in mCRPC after chemotherapy (148 vs 109 months HR 065 p lt 0001)Improved TTP prior to chemotherapy (165 vs 83 months HR 053 p lt 0001)

Fluid retention hypokalemia nonspecific cardiac abnormalities abnormal liver function tests hot flashes and hypertension

[1819101]

Enzalutamide Androgen receptor

Approved by the FDA for the treatment mCRPC postchemotherapyAfter chemotherapy improved median OS 184 vs 136 months (HR 063 p lt 0001)Awaiting final data in Phase III study prechemotherapy

Fatigue diarrhea hot flashes and mild musculoskeletal pain

[26]

TAK-700 CYP17 inhibitor In Phase III trials in mCRPC23 out of 39 patients had a PSA decline of ge90

Fatigue diarrhea and hypertension reported in early studies

[28]

ARN-509 Androgen receptor

In Phase III testing in mCRPC Fatigue nausea and pain reported in early studies

[106]
























[42]




[43]




[49]

































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[49]

































[66]



















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[42]




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[49]

































[66]



















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[66]



















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[66]



















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[66]



















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Documents

Recent advances revolutionize treatment of metastatic prostate cancer