Review Article

Novel Therapeutic Strategies for Castration Resistant ProstateCancer: Inhibition of Persistent Androgen Production andAndrogen Receptor Mediated Signaling

Arturo Molina*,† and Arie BelldegrunFrom the OrthoBiotech Oncology Research and Development, A Unit of Cougar Biotechnology and Institute of UrologicOncology, David Geffen School of Medicine at University of California-Los Angeles (AB), Los Angeles, California

Purpose: Androgen receptor signaling remains essential for many prostate can-cers that have progressed despite androgen deprivation therapy. After medical orsurgical castration persistent though not insignificant low levels of androgens areproduced from nongonadal sources, such as the adrenal glands. Some castrationresistant prostate cancers acquire the ability to convert adrenal steroids toandrogens, maintaining levels sufficient to activate androgen receptor. Inhibitionof persistent androgen production and androgen receptor mediated signaling arerelevant therapeutic strategies for castration resistant prostate cancer.Materials and Methods: The scientific foundation of and clinical experience withsecondary hormonal therapy as well as the development of new investigationalagents for castration resistant prostate cancer, specifically selective cytochromep450 17 inhibitors and second generation antiandrogens, are discussed.Results: Selective inhibition of cytochrome p450 17 has emerged as an importanttherapeutic pathway for castration resistant prostate cancer. The selective cyto-chrome p450 17 inhibitor abiraterone acetate showed promising activity andtolerability in phase I-II trials. Phase III studies are underway in men withchemotherapy naïve castration resistant prostate cancer as well as those withprogression after docetaxel based chemotherapy. TAK-700 and TOK-001 (for-merly VN124-1) are novel selective cytochrome p450 17 inhibitors that recentlyentered phase I/II evaluation. MDV3100 is a second generation antiandrogenthat blocks androgen receptor signaling by inhibiting nuclear translocation of theligand-receptor complex. Clinical data on MDV3100 are encouraging and supportcontinued phase III study.Conclusions: Novel therapies for castration resistant prostate cancer that targetpersistent androgen production and androgen receptor mediated signaling havedemonstrated promising activity in many men with castration resistant prostatecancer and may redefine the clinical management of these patients.

Abbreviations

and Acronyms

AAWD � antiandrogenwithdrawal

ACTH � adrenocorticotropichormone

ADT � androgen deprivationtherapy

AR � androgen receptor

CRPC � castration resistantprostate cancer

CYP17 � cytochrome p450 17

DES � diethylstilbestrol

DHEA � dehydroepiandrostenedione

LH � luteinizing hormone

PSA � prostate specific antigen

TTPP � time to PSA progression

Submitted for publication March 17, 2010.* Correspondence: OrthoBiotech Oncology Re-

search and Development, A Unit of Cougar Biotech-nology, 10990 Wilshire Blvd., Suite 1200, Los An-geles, California 90024 (telephone: 310-943-8040,extension 124; e-mail: AMolina7@its.jnj.com).

† Financial interest and/or other relationshipwith Ortho Biotech and Cougar Biotechnology.

Editor’s Note: This article is the

first of 5 published in this issue

Key Words: prostate, prostatic neoplasms, androgens, abiraterone, castration

1165.

ANDROGEN deprivation therapy is the cor-nerstone of treatment for advanced ormetastatic prostate cancer. Approxi-mately 90% of patients respond to cur-rent first line ADT strategies of medicalcastration with an LH-releasing hor-mone agonist (with or without an antian- drogen) or surgical castration.1 However,

0022-5347/11/1853-0787/0THE JOURNAL OF UROLOGY®

© 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RES

ADT response duration is limited andmost patients experience disease pro-gression within 2 to 3 years. Traditionalsecondary hormonal manipulations, suchas AAWD, or second line antiandrogens,glucocorticoids, estrogens or ketocona-zole, can be of clinical benefit in some

patients after primary ADT failure (see

Vol. 185, 787-794, March 2011Printed in U.S.A.

EARCH, INC. DOI:10.1016/j.juro.2010.10.042

for which category 1 CME credits

can be earned. Instructions for

obtaining credits are given with

the questions on pages 1164 and

www.jurology.com 787

NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCER788

table).1 However, the response and duration of benefittend to decrease with each successive hormonal manip-ulation. Chemotherapy may be an option when hormonetherapy fails. Docetaxel is currently the only agent toshow improvement in overall survival in these patientsas well as in pain and quality of life benefits.2,3 Still, theincremental survival benefit with docetaxel is only about3 months.2–4 Currently median survival after failed ini-tial ADT is approximately 18 months with fewer than20% of patients surviving beyond 3 years.2–4 Prostatecancer remains the second leading cause of cancer re-lated death in men in the United States and the need fornew treatment options is critical.

Disease progression despite medical or surgicalcastration signals the emergence of a prostate can-cer phenotype that can survive and proliferate in alow androgen environment.5 Although it was oncetermed androgen independent or hormone refrac-tory, it is now recognized that a significant propor-tion of these tumors continue to rely on AR signal-ing6 and are more precisely characterized as CRPC.Selective inhibition of persistent androgen produc-tion in CRPC is emerging as a promising therapeuticstrategy. Novel antiandrogens that interfere di-rectly with AR mediated signaling pathways inCRPC are also generating substantial clinical inter-est. The current clinical development of these agents

Select clinical trials of second line therapy with antiandrogens,for CRPC

References Treatment (total daily mg)

2nd Line antiandrogens:Fossa et al9 Flutamide (375), bicalutamide (80)Small et al10 High dose bicalutamide (150)Suzuki et al11 High dose bicalutamide (150)Scher et al12 High dose bicalutamide (200)Kassouf et al13 Nilutamide (200 or 300)

Glucocorticoids:Bubley et al7 Prednisone (10)Small et al14 Prednisone (20)Kantoff et al15 Hydrocortisone (40)Storlie et al16 Hydrocortisone (40)Robertson et al17 Dexamethasone (1.5)Oh et al18 Dexamethasone (0.5-2)Smith et al19 Dexamethasone (1.5)

Estrogens:Kruit et al20 DES (3)Figg et al21 DES (1)

Ketoconazole:Scher et al8 Ketoconazole (1,200) � hydrocortisone � AAChen et al24 Ketoconazole (1,200) � hydrocortisoneLinja et al25 Ketoconazole (600) � hydrocortisoneStanbrough et al26 Ketoconazole (1,200) � hydrocortisoneGregory et al27 Ketoconazole (1,200) � hydrocortisone

Aminoglutehimide:Small et al22 Aminoglutethimide (900) � hydrocortisone �Holzbeierlein et al23 Aminoglutethimide (1,000) � hydrocortisone

* PSA responders combined.

† PSA decrease 80% or greater.

as well as a brief review of hormonal strategies inCRPC to date is summarized. To standardize themeasurement and reporting of the PSA responserate and TTPP clinical studies of these investiga-tional agents are reported using criteria specified inthe Prostate-Specific Antigen Working Group and/orProstate Cancer Clinical Trials Working Group 2guidelines.7,8

TRADITIONAL SECONDARY

HORMONAL THERAPIES FOR CRPC

Cumulative experience with secondary hormonaltherapies provides substantial clinical evidence thatligand mediated AR signaling remains functional ina large proportion of CRPCs. However, except forantiandrogens, current secondary hormonal strate-gies can be considered relatively nonspecific sincethey suppress pituitary-gonadal axis function ornonselectively inhibit adrenal and gonadal steroid-ogenesis. Clinical outcomes of traditional secondaryhormonal therapies in CRPC are briefly summa-rized.

Antiandrogens

The combination of an antiandrogen with gonadalandrogen suppression (combined or maximal andro-gen blockade) or after failed initial androgen sup-

ens and glucocorticoids, and nonspecific androgen inhibitors

No. Pts

PSA Response

% 50% or Greater Median Duration (mos)

193, 39 34, 44 6.6*52 20 Not available31 23 Not available51 24 4.028 28 7.0

101 21 Not available29 34 2.0

230 16 2.381 14 2.327 59 Not available37 62 9.038 61 Not available

42 24 3.821 43 Not available

128 27 8.636 47 6.328 46 7.545 31† Not available50 63 3.5

29 48† 4.035 37 9.0

estrog

WD

AAWD

NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCER 789

pression is often an effective therapeutic maneuver,although responsiveness is inversely related to dis-ease extent. In this setting flutamide produces a50% or greater decrease in PSA in 80% of patientswith localized disease, 54% with metastatic diseaseand 23% with symptomatic metastatic disease.9

Changes in PSA have also been seen upon AAWD, islikely related to the potential of these agents to showpartial agonist activity, particularly in the presenceof altered or mutated AR. In prospective studiesAAWD was associated with a 50% or greater de-crease in PSA in 10% to 15% of patients with pros-tate cancer with responses lasting a median of about6 months.10,11 Changing to an alternate second lineantiandrogen, such as high dose bicalutamide ornilutamide, is associated with a 50% or greater de-crease in PSA in about a third of patients, with amedian response duration of typically between 4 and7 months (see table).11–13

Glucocorticoids

Glucocorticoids, which have a history of use as sup-portive therapy with steroidogenesis suppressiveagents or as a control arm in chemotherapy trials,have modest activity alone in prospective CRPC tri-als. A 50% or greater decrease in PSA was reportedin up to 20% of patients with CRPC on variousprednisone or hydrocortisone regimens and in up to60% on dexamethasone with a response of typicallya median of about 2 months.9,14–16 The mechanismsunderlying the glucocorticoid activity in CRPC arenot well defined and in the absence of comparativerandomized data no 1 particular agent or regimen isconsidered preferable.

Estrogens

Estrogens have long been known to be active againstprostate cancer. The synthetic estrogen DES sup-presses testosterone by decreasing LH-releasinghormone secretion as well as directly affecting pitu-itary LH production. Also, DES has direct cytotoxicactivity in prostate cancer cell lines.17 A 50% orgreater decrease in PSA was reported in 20% to 40%of patients with CRPC treated with DES with amedian response duration of about 4 months (seetable).18,19 However, a substantially increased riskof cardiac and vascular toxicities, including myocar-dial infarction, stroke and pulmonary embolism, isknown to occur with DES and concomitant antico-agulation therapy is recommended with its use inpatients with CRPC.1

Steroidogenesis Inhibitors

Ketoconazole and aminoglutethimide, which are non-specific androgen synthesis inhibitors, have efficacy forCRPC (see table). By blocking the conversion of choles-terol to pregnenolone, aminoglutethimide broadly inhib-

its adrenal steroid synthesis and its use necessitates cor-

ticosteroid supplementation.20 Common adverseeffects include lethargy, nausea, skin rash, pe-ripheral edema, hypothyroidism and increased he-patic enzyme. Aminoglutethimide has largelybeen supplanted by ketoconazole, an azole anti-fungal that inhibits multiple cytochrome p450 en-zymes involved in androgen biosynthesis, includingconversion of cholesterol to pregnenolone, 11�-hy-droxylation and 17�-hydroxylase/C17,20-lyase (CYP17)activity.10 Ketoconazole produces a 50% or greaterdecrease in PSA in approximately 30% to 60% ofCRPC cases with a median response duration ofabout 7 months.10,21,22 In the largest randomizedstudy to date the combination of high dose ketocona-zole with hydrocortisone and AAWD produced a 50%or greater decrease in PSA in 28% of CRPC casescompared to 11% for AAWD alone.10 Deferred use ofketoconazole after AAWD was associated with a 50%or greater decrease in PSA in 32% of patients. Cir-culating androgen, which initially decreased on ke-toconazole therapy, increased at the time of diseaseprogression, indicating failure of this agent to contin-uously suppress androgen biosynthesis. Side effects ofketoconazole, including lethargy, rash, gastrointesti-nal issues and potential adrenal suppression, can of-ten limit treatment duration. Also, as a nonspecificp450 inhibitor ketoconazole has the potential to pro-voke drug-drug interactions by interfering with themetabolism of other drugs, including warfarin andvarious statins.

INSIGHTS INTO ANDROGEN

PRODUCTION AND SIGNALING IN CRPC

AR Signaling

Prostate cancer gene expression studies revealedthat AR activated genes that are initially down-regulated during ADT become reactivated upontransition to CRPC.23 Up-regulation of the AR genecoincides with this transition24 and AR gene ampli-fication has been found in about 30% of CRPCs.25

The importance of ligand mediated AR signaling inCRPC is underscored by findings of frequent ARover expression and heightened AR sensitivity re-lated to increased receptor stabilization, enhancednuclear localization and over expression of nuclearcoactivators.23,25–27 Point mutations may confer ARpromiscuity, permitting activation by nonandro-genic ligands such as progesterone and estradiol.6

These finding support the theory that ligand depen-dent AR signaling may be a primary mediator ofgrowth and survival among CRPCs. Ligand inde-pendent mechanisms may also have a role in persis-tent AR signaling in CRPC, as evidenced by therecent identification of several constitutively active

AR splice variants.28

NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCER790

Persistent Androgen

Production in Castrate Environment

With current ADT strategies the suppression ofgonadal androgen production results in castratetestosterone, defined as less than 50 ng/dl (lessthan 2.0 nM). Despite gonadal androgen suppres-sion, low levels of circulating androgens persist,mainly due to peripheral conversion of adrenalsteroids, and circulating testosterone may be seenat up to 10% of precastration levels.29 Recent find-ings suggest that CRPCs acquire the ability toconvert adrenal steroids to androgens, in essencecreating an intracrine signaling system. Gene up-regulation and expression of enzymes involved inandrogen biosynthesis, including CYP17, havebeen documented in CRPC tissue23,26,30,31 withevidence of intratumor conversion of upstreamprecursors of testosterone and dihydrotestoster-one present at concentrations sufficient to activateAR.32,33 These findings have supported the clinicaldevelopment of novel agents that selectively tar-get persistent androgen production and ligand me-diated AR binding in CRPCs.

Role of CYP17 in Androgen Biosynthesis

Cytochrome p450c17 (CYP17) catalyzes 2 essentialreactions in androgen biosynthesis, including 17�-hydroxylation of C21 steroids and cleavage of theC17,20 bond of C21 steroids.34 These reactions are keyin the biosynthesis of DHEA and androstenedione,precursors of testosterone and estradiol (see figure).The biological consequences of CYP17 inhibition areillustrated by the clinical and biochemical features

Pregnenolone Progesterone

17α-hydroxypregnenolone 17α-hydroxyp

CYP17(17α-hydroxylase)

CYP17(C17,20 lyase)

Dehydroepiandrostenedione(DHEA) Androstenedio

Cholesterol

ACTH

Steroid biosynthesis pathwa

of patients with congenital CYP17 deficiency, a raredisorder characterized by adrenal hyperplasia, andinadequate synthesis of cortisol, androgen and es-trogen, accompanied by impaired sexual develop-ment.34 Because mineralocorticoid biosynthesis isnot impaired and due to the weak glucocorticoidactivity provided by corticosterone, these patients donot have adrenocortical insufficiency. However, inresponse to low circulating cortisol the cortisol-ACTH feedback loop is stimulated, leading to in-creased pituitary release of ACTH. This results inexcess mineralocorticoid production and a clinical syn-drome characterized by hypertension, hypokalemia,fluid overload and renin suppression. This syndrome iseffectively managed by low dose glucocorticoids withor without mineralocorticoid antagonists to suppressACTH release.

SELECTIVE TARGETING

OF CYP17 FOR CRPC

Given its critical role in androgen biosynthesis,CYP17 has generated interest as a relevant biolog-ical target for CRPC. Several novel therapeutic en-tities that selectively inhibit CYP17 are currentlyunder clinical evaluation for CRPC (see Appendix).

Abiraterone Acetate

Abiraterone is a highly potent, selective, irreversibleinhibitor of CYP17.35 Abiraterone prevents conver-sion of pregnenolone to DHEA and progesterone toandrostenedione in the testes and adrenal glands.Abiraterone also appears to suppress de novo andro-

Corticosterone Aldosterone

terone Cortisol

Testosterone 5α-dihydrotestosterone

Estrogens

(Mineralocortocoids)

(Glucocortocoids)

roges

ne

ys and role of CYP17

NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCER 791

gen production in prostate tumors, as evidenced byinhibition of CRPC growth in xenograft models de-void of testicular and adrenal androgens.36 Unlikenonspecific CYP17 inhibitors such as ketoconazole,abiraterone was not anticipated to impair mineralo-corticoid synthesis, providing potential improvedclinical tolerability.

Early clinical evaluation of oral abiraterone ac-etate in noncastrate men showed that initial an-drogen suppression was soon overcome by a com-pensatory surge in luteinizing hormone and, assuch, development focused on a castrate popula-tion.37 In phase I studies abiraterone acetate fur-ther decreased castrate testosterone to concentra-tions below detection limits.38,39 Other systemiceffects consistent with selective CYP17 inhibitionincluded stimulation of ACTH release in responseto decreased cortisol and resulting increases inmineralocorticoid precursors (deoxycorticosteroneand corticosterone) with little effect on aldoste-rone due to a negative feedback loop. As learned inpatients with congenital CYP17 deficiency, addinga supplemental glucocorticoid such as dexameth-asone or prednisone suppresses ACTH release andis often effective for signs of mineralocorticoid ex-cess, including hypertension, hypokalemia andfluid retention. Pharmacokinetic analysis sug-gested that interaction with food, such as a highfat meal, tended to increase drug exposure, al-though these findings were quite variable. Assuch, abiraterone acetate is given in a fastingstate to maintain drug exposure as consistently aspossible.

In phase I/II studies in men with chemotherapynaïve CRPC in whom multiple prior hormonal ther-apies had failed the pharmacodynamic effects of abi-raterone acetate appeared to plateau at a dose of 750to 1,000 mg, leading to the selection of 1,000 mg forcontinued phase II evaluation.38–41 Common ad-verse events of consistent mineralocorticoid excessincluded hypertension, hypokalemia and edema,which responded to management by the selectivemineralocorticoid receptor antagonist eplerenone orlow dose corticosteroids. Spironolactone was specif-ically avoided because of its potential androgenicproperties. Other common adverse events were fa-tigue, headache, nausea and diarrhea. No dose lim-iting toxicity was seen with the administration of upto 2,000 mg abiraterone acetate daily.

In a cohort of 42 patients treated with abirateroneacetate at the phase II dose of 1,000 mg 28 (67%) hada 50% or greater PSA decrease with a greater than90% decrease in 8 (19%).40 Objective partial re-sponses were seen in 9 of 24 patients (37.5%) withmeasurable disease. Median TTPP overall was 225days (95% CI 162 to 287) with a median TTPP of 253

days (95% CI 122 to 383) in patients with a 50% or

greater decrease in PSA. Of 30 patients given dexa-methasone 0.5 mg at the time of progression, whichwas permitted by protocol, a secondary PSA re-sponse of 50% or greater was noted in 10 (33%). Ofinterest, steroid levels downstream of CYP17 did notincrease at the time of disease progression, suggest-ing sustained CYP17 inhibition.38

Prior ketoconazole was permitted in the phase Iportion of the second phase I/II study.39 Of 33phase I patients 19 (58%) had a 50% or greaterdecrease in PSA, including 10 of 19 (53%) withprior ketoconazole exposure. These findings sug-gested a potential lack of cross resistance withprior ketoconazole. The phase II portion of thisstudy added prednisone 5 mg twice daily to abi-raterone acetate 1,000 mg daily and excluded pa-tients with prior ketoconazole exposure.41 Prelim-inary findings indicated a 50% or greater PSAdecrease in 29 of 33 patients (88%) with a medianTTPP of 337 days (95% CI 280 days, never at-tained). The use of prednisone markedly de-creased the incidence and severity of hypokale-mia, hypertension and fluid retention. Except forsingle incidences of grade 3 hypertension and hy-pokalemia, most adverse events were grade 1 andno grade 4 events attributable to mineralocorti-coid excess were seen.

Phase II studies have evaluated abiraterone ace-tate as monotherapy and combined with low doseprednisone in men with CRPC and disease progres-sion after docetaxel chemotherapy. In each studypatients were heavily pretreated, and multiple hor-monal therapies and up to 2 prior chemotherapieshad failed. With abiraterone acetate monotherapy a50% or greater decrease in PSA was seen in 24 of 47patients (51%) with a median TTPP of 169 days(95% CI 130 to 281).42 Objective partial responseswere seen in 6 patients (13%) and disease stabiliza-tion was noted in 25 (53%). In 11 patients (23%)there was improved performance status, a potentialsurrogate indicator of clinical benefit. Consistentwith expectations, adverse events included hypoka-lemia in 55% of cases, hypertension in 17% and fluidretention in 15%, which responded to managementby eplerenone or low dose corticosteroids. Abi-raterone acetate combined with prednisone pro-duced a 50% or greater decrease in PSA in 24 of 58patients (41%), including 8 of 27 (30%) who wereketoconazole pretreated and 16 of 31 (52%) whowere ketoconazole naïve.43 Median TTPP was 99days (95% CI 57 to 169) in patients with prior keto-conazole exposure and 198 days (95% CI 82 to notevaluable) in ketoconazole naïve patients. The com-bination was well tolerated with adverse events con-sisting of primarily grade 1 or 2 hypokalemia, hy-pertension and fluid retention. Abiraterone acetate

is currently being evaluated in 2 randomized, mul-

NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCER792

ticenter, phase III studies of CRPC and accrual tothese studies is complete.

Features and characteristics that may predict re-sponse to abiraterone acetate are under evaluation.Pretreatment serum DHEA, DHEA-sulfate andro-stenedione and estradiol correlate with the proba-bilities of a 50% or greater PSA decrease andTTPP.44 In patients with a baseline circulating tu-mor cell count of 5/7.5 ml or greater a decrease toless than 5/7.5 ml was associated with a 50% orgreater decrease in PSA.42,43 Correlations betweenserum testosterone levels and those in the tumormicroenvironment in patients with CRPC with bonemetastasis are also being explored.44 Preliminaryfindings suggest that higher testosterone in the tu-mor microenvironment (bone marrow) may correlatewith an increased likelihood of a response. Theseobservations support a role for intracrine androgenproduction and persistent AR signaling in CRPC,and suggest a possible predictive indicator for re-sponse.

CYP17 Inhibitors TAK-700 and TOK-001

TAK-700 and TOK-001 (formerly VN/124-1) are se-lective CYP17 inhibitors currently in phase I/II de-velopment (see Appendix). Preliminary phase I re-sults with TAK-700, an oral selective C17,20-lyaseinhibitor, summarized findings with dose levels of100 through 600 mg twice daily as well as 400 mgtwice daily combined with low dose prednisone in 26patients with metastatic CRPC.45 No dose limitingtoxicity was seen. Fatigue was the most commontreatment related adverse event, as seen in 16 pa-tients (62%), including 3 with grade 3 or greaterevents at the 600 mg dose. Other common treatmentrelated adverse events were nausea in 38% of cases,constipation in 35%, anorexia in 35% and vomitingin 30%. Decreases in median testosterone from 4.9to 0.6 ng/dl and in DHEA-sulfate androstenedionefrom 53.8 to less than 0.1 �g/dl were seen at the 400mg dose. A blunted cortisol response after ACTHstimulation was seen in 2 of 7 patients at the 400 mgdose and in all 5 at the 600 mg dose. Doses at orabove 300 mg twice daily produced a 50% or greaterdecrease in PSA in 11 of 14 patients (70%), of whom4 (29%) had a 90% or greater PSA decrease. Contin-ued phase II evaluation of TAK-700 at the 400 mgtwice daily dose, including the need for concomitantprednisone, in men with metastatic CRPC is ongo-ing. Also, a phase II study of TAK-700 in men withnonmetastatic CRPC with increasing PSA has be-gun accrual.

In preclinical experience TOK-001 selectively in-hibited 17�-hydroxylase/C17,20-lyase activity anddown-regulated AR expression.46 In the LAPC4prostate cancer xenograft model TOK-001 combined

with castration inhibited tumor growth and signifi-

cantly down-regulated AR protein expression, incontrast to findings with castration alone or bicalu-tamide, which showed up-regulation of AR expres-sion. Phase I/II evaluation of TOK-001 in CRPC wasinitiated in late 2009.

NOVEL AR ANTAGONISTS FOR CRPC

Second Generation Antiandrogen MDV3100

AR over expression is known to be a mechanism ofantiandrogen resistance in CRPC. Also, the partialagonist activity of current first generation antian-drogens such as bicalutamide can be a factor intumor progression. MDV3100 is a novel second gen-eration antiandrogen that shows selective, potentaffinity for AR while being devoid of any agonist ARactivity in CRPC models.47 Compared to bicaluta-mide MDV3100 has greater binding affinity for AR.In CRPC cell lines MDV3100 effectively inhibits nu-clear translocation and DNA binding to androgenresponse, leading to the induction of apoptosis. Intumor xenograft models known to over express ARtreatment with MDV3100 led to substantial tumorregression while growth suppression was more mod-est.

MDV3100 was clinically evaluated in a phase I/IImulticenter study in 140 patients with progressivemetastatic CRPC with oral dose escalations of 30 to600 mg daily.48 The study population was relativelyheavily pretreated with failure of at least 2 priorhormonal therapies in most patients, prior keto-conazole exposure in 63 (45%) and failure of at least1 prior chemotherapy in 75 (54%). The most commontreatment related adverse event with MDV3100 wasfatigue, which had an onset of approximately 4weeks with timing that corresponded to the achieve-ment of steady-state drug concentrations. Grade 3/4adverse events were seen predominantly at a dose of360 mg or greater, including fatigue in 11% of pa-tients, which generally responded to dose reduction,asthenia in 2% and seizures in 2%. Due to tolerabil-ity issues at doses above 360 mg and the potentialconcern for seizures a maximum tolerated dose of240 mg was selected for sustained treatment. Effi-cacy was observed across all dose levels and ap-peared to be dose dependent, attaining a plateau atbetween 150 and 240 mg daily. Overall a 50% orgreater PSA decrease was seen in 78 patients (56%)with objective partial responses in 13 (22%) withmeasurable disease. A similar 50% or greater PSAdecrease was seen in patients parsed by prior che-motherapy exposure and extent of prior hormonaltherapy, although a lower rate was seen in patientspreviously treated with ketoconazole. Overall me-dian TTPP was 224 days (95% CI 147 to 315) with amedian of 147 (95% CI 140 to 231) and 287 days

(95% CI 203 to 427) in patients with and without

NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCER 793

prior chemotherapy exposure, respectively. Also,49% of patients with an unfavorable circulating tu-mor cell count (5/7.5 ml or greater) at baseline hadconversion to favorable counts, of whom 19 (76%)also had a 50% or greater maximum PSA decrease.Currently MDV3100 at a dose of 160 mg is underphase III evaluation in patients with CRPC whowere previously treated with docetaxel.

AR Inhibitor BMS-641988

BMS-641988 is a highly potent AR inhibitor thatwas specifically designed based on AR crystal struc-ture.49 Compared to bicalutamide BMS-6410988showed higher binding affinity and greater inhibi-tion of AR mediated signaling in preclinical models.Two phase I studies of BMS-641988 in CRPC arecomplete but results have not yet been reported.

CONCLUSIONS

A significant proportion of CRPCs continue to rely

on ligand mediated AR signaling for growth and

REFERENCES

tate cancer. Clin Cancer Res 2006; 12: 1665. Genitourinary Group. J Clin

survival. Adaptive mechanisms, including up-regu-lation of AR expression and enhanced receptor sen-sitivity, permit tumor growth in the castrate envi-ronment. In castration resistant prostate tumortissues the expression of enzymes involved in andro-gen biosynthesis suggests that these tumors mayalso develop intracrine signaling mechanisms.Novel agents that target CYP17 and selectively in-hibit persistent androgen production show promisefor CRPC treatment. Also, second generation anti-androgens such as MDV3100 offer another means toaddress persistent AR signaling in CRPC. Based onencouraging clinical results to date it seems likelythat these new classes of agents will substantiallychange the treatment and clinical outlook in manymen with CRPC, particularly those unwilling to ac-cept or unable to tolerate cytotoxic chemotherapy.

ACKNOWLEDGMENTS

Christine Gutheil and Karim Chamie assisted with

the manuscript.

APPENDIXClinical development status of novel androgen synthesis inhibitors and second generation antiandrogens for CRPC

Class/Agent Target Phase Status

Androgen biosynthesis inhibitors:Abiraterone acetete CYP17 (17-�-hydroxylase/C17,20-lyase) IIITOK-001 (formerly VN/124-1) CYP17 (17-�-hydroxylase/C17,20-lyase), selective AR modulator I/IITAK-700 CYP17 (C17,20-lyase) I/IIAntiandrogens:MDV3100 AR binding/nuclear translocation I/IIBMS-641988 AR binding I

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