Phase I/II Trial of Orteronel (TAK-700) an Investigational ... · Poster presented at the Endocrine Society's 94th Annual Meeting & Expo. 2012 Jun 23–26, Houston, TX. Corresponding

Cancer Therapy: Clinical

Phase I/II Trial of Orteronel (TAK-700)—an Investigational17,20-Lyase Inhibitor—in Patients with MetastaticCastration-Resistant Prostate Cancer

Robert Dreicer1, David MacLean2, Ajit Suri2, Walter M. Stadler4, Daniel Shevrin5, Lowell Hart7,Gary R. MacVicar6, Omid Hamid8, John Hainsworth10, Mitchell E. Gross9, Yuanjun Shi2,Iain J. Webb3, and David B. Agus9

AbstractPurpose: The androgen receptor pathway remains active in men with prostate cancer whose disease has

progressed following surgical or medical castration. Orteronel (TAK-700) is an investigational, oral, nonste-

roidal, selective, reversible inhibitor of 17,20-lyase, a key enzyme in the production of androgenic hormones.

Experimental Design: We conducted a phase I/II study in men with progressive, chemotherapy-na€�ve,

metastatic castration-resistant prostate cancer, and serum testosterone <50 ng/dL. In the phase I part,

patients receivedorteronel 100 to600mg twice daily or 400mg twice adayplus prednisone 5mg twice aday.

Inphase II, patients receivedorteronel 300mg twice aday, 400mg twice adayplus prednisone, 600mg twice

a day plus prednisone, or 600 mg once a day without prednisone.

Results: Inphase I (n¼ 26), nodose-limiting toxicitieswereobserved and13of 20 evaluable patients (65%)

achieved�50%prostate-specific antigen (PSA) decline frombaseline at 12weeks. In phase II (n¼ 97), 45 of 84

evaluable patients (54%) achieved a�50% decline in PSA and at 12 weeks, substantial mean reductions from

baseline in testosterone (�7.5 ng/dL) and dehydroepiandrosterone-sulfate (�45.3 mg/dL) were observed.

Unconfirmed partial responses were reported in 10 of 51 evaluable phase II patients (20%). Decreases in

circulating tumor cells were documented. Fifty-three percent of phase II patients experienced grade�3 adverse

events irrespective of causality; most common were fatigue, hypokalemia, hyperglycemia, and diarrhea.

Conclusions: 17,20-Lyase inhibition by orteronel was tolerable and results in declines in PSA and

testosterone, with evidence of radiographic responses. Clin Cancer Res; 20(5); 1335–44. �2014 AACR.

IntroductionTestosterone suppression through medical or surgical

castration has been the standard of care in advanced pros-tate cancer since the seminal work of Huggins and Hodges(1). Androgen deprivation therapy, while highly effective

short term, is not curative with the majority of patientseventually developing disease progression (2).

In CRPC, intraprostatic dihydrotestosterone, and testos-terone levels remain sufficiently elevated to activate theandrogen receptor despite castrate serum levels with

Authors' Affiliations: 1Cleveland Clinic, Cleveland, Ohio; 2Takeda Phar-maceuticals International Company; 3Millennium: The Takeda OncologyCompany, Cambridge, Massachusetts; 4University of Chicago, Chicago;5NorthShore University Health System, Evanston; 6Northwestern Univer-sity Feinberg School of Medicine, Chicago, Illinois; 7Florida Cancer Spe-cialists, Fort Myers, Florida; 8The Angeles Clinic & Research Institute, LosAngeles; 9University of Southern California Westside Cancer Center, Bev-erly Hills, California; and 10Sarah Cannon Cancer Research Institute,Nashville, Tennessee

Note: Supplementary data for this article are available at Clinical CancerResearch Online (http://clincancerres.aacrjournals.org/).

Prior presentations: Agus DB, Stadler WM, Shevrin DH, et al. Safety,efficacy, and pharmacodynamics of the investigational agent TAK-700 inmetastatic castration-resistant prostate cancer (mCRPC): updated datafrom a phase I/II study. ASCOMeeting Abstracts 2011;29 (15_suppl):4531;Agus DB, Stadler WM, Shevrin D, et al. Safety, efficacy, and pharmaco-dynamics of the investigational agent TAK-700 in metastatic castration-resistant prostate cancer (MCRPC): updateddata fromaphase I/II study. Inproceedings of the 34th Congresso Brasileiro de Urologia. 2011 Nov 22–26. Florian�opolis, Santa Catarina, Brazil; Agus DB, Stadler WM, Shevrin D,et al. Safety, efficacy, and pharmacodynamics of the investigational agentorteronel (TAK-700) in metastatic castration-resistant prostate cancer

(mCRPC): updated data from a phase I/II study. In proceedings of the20th Malaysian Urological Conference-Asia Pacific Society of Uro-Oncol-ogy Conference. 2011 Nov 25–27. Kuala Lumpur, Malaysia; Gross M,Shevrin D, Dreicer R, et al. Phase I/II study of TAK-700, an investigational17,20-lyase inhibitor, in chemotherapy-naïve patients with metastaticcastration-resistant prostate cancer (mCRPC): safety, efficacy, and eval-uation of circulating tumor cells (CTC). In proceedings of the 3rd EuropeanMultidisciplinary Meeting on Urological Cancers (EMUC). 2011 Nov 4–6.Barcelona, Spain; Agus DB, Stadler WM, Shevrin D, et al. Safety, efficacy,and pharmacodynamics of the investigational agent orteronel (TAK-700) inmetastatic castration-resistant prostate cancer (mCRPC): updated datafrom a phase I/II study. ASCO-GU Meeting Abstracts 2012; J Clin Oncol2012;30 (suppl 5;abstr 98); MacLean DB, Stadler WM, Shevrin D, et al.Selective inhibition of androgen synthesis by orteronel (TAK-700), aninvestigational 17,20-lyase inhibitor, in men with metastatic castrate resis-tant prostate cancer (mCRPC). Poster presented at the EndocrineSociety's 94th Annual Meeting & Expo. 2012 Jun 23–26, Houston, TX.

Corresponding Author: Robert Dreicer, 9500 Euclid Avenue R35, Cleve-land, OH 44195. Phone: 216-445-4623; Fax: 216-445-2360; E-mail:[email protected]

doi: 10.1158/1078-0432.CCR-13-2436

�2014 American Association for Cancer Research.

ClinicalCancer

Research

www.aacrjournals.org 1335

Research. on September 29, 2020. © 2014 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Published OnlineFirst January 13, 2014; DOI: 10.1158/1078-0432.CCR-13-2436

http://clincancerres.aacrjournals.org/

evidence for persistent expression of androgen-synthesizingenzymes and ongoing androgen synthesis within prostatetumors collected from castrated patients (3, 4). The mostcommon mechanism of early resistance is androgen recep-tor upregulation, which increases sensitivity to low remain-ing androgens (5). These findings have fostered an interestin CYP17A1 inhibition to deplete both intratumoral andextragonadal sources of steroid ligands (6, 7). CYP17A1 isan essential enzyme for biosynthesis/production of steroi-dal hormones, and has both 17,20-lyase and 17a-hydrox-ylase activities (8–10). This pathway’s importance in CRPChas been reinforced by positive phase III trials with abir-aterone acetate (Zytiga; refs. 11 and 12) and androgenreceptor antagonist enzalutamide (Xtandi; ref. 13). Bothagents have demonstrated increased overall survival inpatients with advanced mCRPC previously treated withdocetaxel (11, 13).

Orteronel (TAK-700) is a nonsteroidal, selective, revers-ible inhibitor of 17,20-lyase. Five-fold selectivity of orter-onel for 17,20-lyase activity over 17a-hydroxylase activityof CYP17A1 has been demonstrated in preclinical studies(14). Orteronel may therefore result in near full inhibitionof androgen synthesis with only partial inhibition of 17a-hydroxylase activity, allowing adrenal cortisol synthesis tocontinue—an important consideration as inhibition there-of can lead to mineralocorticoid excess. Preclinical datashow that orteronel reduces andmaintains low testosteronelevels (14). This is the first clinical report to characterize thesafety and efficacy of orteronel, based on findings from thephase I/II study in men with chemotherapy-na€�ve mCRPC.

Patients and MethodsPatients

Patients were recruited from 11 U.S. centers. The studywas conducted in accordance with the Declaration of Hel-sinki/Good Clinical Practice, Institutional Review Boardsapproved all aspects of the study, and all participantsprovided written informed consent. Eligibility included

pathologically confirmed prostate adenocarcinoma withradiographically confirmed metastatic disease progressiondespite castrate levels of testosterone (<50 ng/dL), an East-ernCooperativeOncologyGroupperformance status of 0 to2, and prostate-specific antigen (PSA)�5 ng/mL. Eligibilityalso required adequate hematologic, cardiovascular, renal,and hepatic function. Patients also had to be free of signif-icant prostate cancer–related symptoms, including opioid-requiring bone pain. Patients could have received amino-glutethimide, ketoconazole, or radiation therapy, but notwithin 30 days before first dose of study drug.

Study designPhase I dose escalation followed a standard 3þ3 schema:

patients received open-label single-agent orteronel in 28-day cycles (continuous dosing) at 1 of 5 dose levels: 100,200, 300, 400, or 600 mg twice a day. An additional cohortalso received orteronel 400 mg twice a day plus prednisone5 mg twice a day.

In phase II, patients received open-label orteronel dailywithout food restrictions in 28-day cycles in 4 parallel dosecohorts: 300 mg twice a day, 400 mg twice a day plusprednisone 5 mg twice a day, 600 mg twice a day plusprednisone 5 mg twice a day, or 600 mg every day in themorning. These regimens were selected for further explora-tion based on (i) frequency of PSA responses at doses�300mg twice a day; (ii) thedetermination that any dose regimen�400mg twice a daywould likely benefit fromconcomitantprednisone administration; and (iii) to test whether admin-istration of 600mg every day was similarly efficacious to anequal but divided daily dose.

Patients continued to receive orteronel until PSA progres-sion (prostate cancer working group 2 (PCWG2; ref. 15),objective disease progression by Response Evaluation Cri-teria in Solid Tumors (RECIST; ref. 16), bone scan orinvestigator opinion, or occurrence of unacceptable toxic-ity. At investigator assessment and request, patients withPSA progression without new symptoms were allowed toremain on study drug.

The primary objective was to assess safety and tolera-bility. Secondary objectives included assessment of effi-cacy, as shown by PSA response and/or objective diseaseresponse; assessment of endocrine responses to orteronel[testosterone, dehydroepiandrosterone-sulfate (DHEA-S)and adrenocorticotropic hormone (ACTH)-adrenal axis;pharmacodynamics]; and pharmacokinetics of orteronel.Exploratory objectives included enumeration of circulat-ing tumor cells (CTC).

AssessmentsSampling timepoints are shown in Supplementary Table

S1. Adverse events were graded using National CancerInstitute Common Terminology Criteria for adverse events(NCI-CTCAE) v3.0. During phase I, maximum-tolerateddose (MTD) was defined as the dose level immediatelybelow that at which �2 of up to 6 patients experienceddose-limiting toxicities (DLT) in cycle 1. DLTs were definedas any drug-related grade �3 adverse event or any cardiac-

Translational RelevanceThis phase I/II trial of orteronel tests the concept of

selective inhibition of the androgen synthesis pathwaycombined with continued adrenal cortisol synthesis bytargeting the 17,20-lyase activity over the 17a-hydroxy-lase activity of CYP17A1 in the treatment of men withmetastatic castration-resistant prostate cancer (mCRPC)and increased sensitivity to low remaining androgens.Alleviating the effects of early castration resistance cancontribute to the development of more effective orter-onel-based treatment for mCRPC. In this trial, we con-ducted dose escalation studies to evaluate the clinicalbenefits and pharmacokinetics of orteronel. This is thefirst clinical manuscript to report the safety and efficacyof orteronel. Our findings are currently being validatedin ongoing phase III trials in patients with mCRPC.

Dreicer et al.

Clin Cancer Res; 20(5) March 1, 2014 Clinical Cancer Research1336




related adverse event. Documented fatigue events werebased on CTC criteria and not a formal patient reportedoutcome; thus, mechanism of fatigue (central nervoussystem central vs. neuromuscular) requires additionalstudy. Pharmacokinetic parameters were determined fromplasma concentration–time data using standard noncom-partmental methods.Radiologic response was assessed according to modified

RECIST v1.0, with nonconfirmation per RECIST v1.1. Bonescan progression was assessed per RECIST rather than perPCWG2 criteria, which came into practice after the initia-tion of this study. The endocrine and cortisol assays inphases I and II, respectively, were performed at differentlaboratories using assays with different lower limits ofquantification. In phase II and in phase I patients ongoingafter the start of phase II, liquid chromatography/massspectrometry (LC/MS) was used for evaluation of testoster-one, DHEA-S, and other steroid hormones, except cortisol.The validated LC/MS testosterone assay was performed byEsoterix Laboratories (LabCorp); between different labora-tories, the lower limits of detection varied during the studybetween 50 and 200 pg/mL (0.05–0.2 ng/dL), and resultsbelow 0.2 ng/dL should be interpreted with caution.CTCs were enumerated using validated Veridex Cell-

Search methodology (17). CTC counts were assessed asboth dichotomous (<5 vs. �5 per 7.5 mL of whole blood)and quantitative variables (18, 19).

Statistical methodsPlanned enrolment was up to 123 patients: up to 35 in

phase I and 88 (22 per dose group) in phase II to give 20response-evaluable patients per group. The phase II portionhad 85% power and a one-sided significance of 0.05 for

each twice a day dose group to detect a 50% PSA response(PSA50) rate at 12 weeks versus 20% for null hypothesis.The 600 mg every day group, added later to evaluatepotential differences versus 300 mg twice a day, had 80%power to detect a PSA50 response. Phase II patients treatedat dose levels also evaluated in the phase II component ofthe trial were included in the phase II analysis.

Standard summary statistics were used for PSA and endo-crine changes over time, as well as for observed values andchange from baseline in CTCs. Time to disease progression(duration from the date of first dose until the date of the firstdocumented evidence of progressive disease) was analyzedusing Kaplan–Meier methodology.

ResultsPatients

Twenty-six patients were enrolled in the phase I portionof the study and, because of slight overenrolment, 97 in thephase II portion. Enrollment commenced on April 2, 2008and the last patient completed 6 months of treatment onMarch 15, 2011. Baseline demographics and patient char-acteristics are shown in Table 1.

Phase I patients received a median of 7 (range 0–36) 28-day treatment cycles. Twenty-two patients (85%) have dis-continued therapy because of: adverse events in 8 patients,objective disease progression in 7, PSA progression in 3,voluntary withdrawal in 3, and other reasons in 1. Fourpatients remain on therapy (1 each at 200, 300, 600 mgtwice a day, and 400mg twice a day plus prednisone) with amaximum duration of 1,030 days’ treatment (>36 cycles).Phase II patients completed a median of 9 (range 0–22)treatment cycles. At the time of analysis, 37 patientsremained on treatment, with a maximum duration of

Table 1. Patient demographics and disease characteristics

Characteristic Phase I (N ¼ 26) Phase II (N ¼ 97)

Median age, y (range) 70 (46–87) 70 (49–90)Race, n (%)White 22 (85) 83 (86)Black/African American 3 (12) 8 (8)Asian 1 (4) 3 (3)Native Hawaiian/other Pacific Islander 0 1 (1)Unknown 0 2 (2)

Median PSA at baseline, ng/mL (range) 57.4 (6.4–3,812.0) 44.3 (5.9–820.0)Disease stage at diagnosis, n (%)a

1 2 (8) 8 (8)2 7 (27) 14 (14)3 4 (15) 19 (20)4 3 (12) 15 (16)Unknown 10 (39) 39 (40)

Prior adrenal-directed therapyb, n (%) 12 (46) 29 (30)

aData missing for 2 patients in the phase II portion.bAminoglutethimide, abiraterone, ketoconazole.

Phase I/II Trial of 17,20-Lyase Inhibitor Orteronel in mCRPC

www.aacrjournals.org Clin Cancer Res; 20(5) March 1, 2014 1337




Tab

le2.

Mos

tco

mmon

trea

tmen

t-relatedad

verseev

ents

[reportedat

anygrad

ein

�20%

orat

grad

e�3

in�5

%of

pha

seIp

atientsov

erall

(n¼

26),or

reportedat

anygrad

ein

�15%

orat

grad

e�3

in�5

%of

pha

seIIpatientsov

erall(n¼

97)]

Orterone

lalone

(steroid-free)

Orterone

lpluspredniso

ne

Pha

seI

Pha

seII

Pha

seII

Pha

seI

Pha

seII

Pha

seII

100–

600mgTwicea

day

(n¼

20)

300mgtw

iceaday

(n¼

23)

600mgev

eryday

(n¼

24)

400mgtw

iceaday

pluspredniso

ne(n

¼6)

400mgtw

iceaday

pluspredniso

ne(n

¼24

)

600mgtw

iceaday

pluspredniso

ne(n

¼26

)

Patientswith

adve

rseev

ents,n

(%)

Any

grade

Grade�3

Any

grade

Grade�3

Any

grade

Grade�3

Any

grade

Grade�3

Any

grade

Grade�3

Any

grade

Grade�3

Any

drug-related

adve

rseev

ent

19(95)

11(55)

23(100

)8(35)

24(100

)4(17)

6(100

)2(33)

22(92)

8(33)

25(96)

10(39)

Fatig

ue15

(75)

3(15)

17(74)

1(4)

18(75)

3(13)

2(33)

1(17)

16(67)

3(13)

20(77)

4(15)

Nau

sea

9(45)

1(5)

10(44)

—8(33)

—1(17)

—10

(42)

—15

(58)

2(8)

Hea

dac

he8(40)

—9(39)

—4(17)

—1(17)

—7(29)

—2(8)

—

Con

stipation

6(30)

—7(30)

—5(21)

—3(50)

—6(25)

—11

(42)

—

Diarrhe

a4(20)

3(15)

7(30)

1(4)

5(21)

1(4)

1(17)

—6(25)

1(4)

7(27)

—

Ano

rexia

9(45)

—5(22)

—3(13)

—1(17)

—6(25)

—8(31)

1(4)

Dizzine

ss2(10)

—5(22)

—2(8)

—2(33)

—4(17)

—7(27)

—

Hot

flus

h2(10)

—4(17)

—1(4)

—1(17)

—4(17)

—6(23)

—

Hyp

okalem

ia2(10)

—4(17)

2(9)

2(8)

——

—1(4)

1(4)

3(12)

3(12)

Mus

clesp

asms

——

4(17)

—2(8)

—1(17)

—5(21)

—6(23)

—

Vom

iting

6(30)

1(5)

2(9)

—3(13)

—1(17)

1(17)

1(4)

—1(4)

1(4)

Prolong

edQTinterval

5(25)

1(5)

4(17)

—1(4)

—1(17)

—1(4)

——

—

Hyp

erglyc

emia

1(5)

—4(17)

1(4)

3(13)

—1(17)

—4(17)

1(4)

4(15)

1(4)

Hyp

ertens

ion

6(30)

2(10)

5(22)

—1(4)

——

—2(8)

—5(19)

1(4)

Lympho

pen

ia6(30)

2(10)

3(13)

1(4)

1(4)

——

—2(8)

—2(8)

1(4)

Increa

sedlip

ase

2(10)

2(10)

——

——

——

——

——

Any

drug-relatedSAE

4(20)

—1(4)

—1(4)

—1(17)

—2(8)

—3(12)

—

NOTE

:Disco

ntinua

tions

bec

ause

ofdrug-relatedad

verseev

ents

inpha

seIIwerefatig

ue(n

¼3),d

ecreas

edperform

ance

status

(n¼

1),d

iarrhe

a(n

¼2),n

ause

a(n

¼1),[LV

]EF

dys

func

tion(n

¼2),s

omno

lenc

e(n

¼1),a

cute

rena

lfailure

(n¼

1),d

yspne

a(n

¼1),m

aculop

apular

rash

(n¼

1);a

ndbec

ause

ofall-ca

usead

verseev

ents

wereed

ema(n

¼1),

resp

iratory

arrest

(n¼

1),s

pinal

cord

compress

ion(n

¼1),b

acteremia

(n¼

1),s

uprave

ntric

ular

extras

ystoles(n

¼1),a

rthralgia(n

¼1),p

ain(n

¼1),m

eningiom

a(n

¼1).

Abbreviation:

[LV]EF,

leftve

ntric

ular

ejec

tionfrac

tion.

Dreicer et al.





638days’ treatment in apatient receiving400mg twice adayplus prednisone (>22 cycles); as of April 2013, 6 patients areongoing. Sixty patients (62%) discontinued treatmentbecause of: adverse event (n ¼ 18, of which 11 wereconsidered drug related), objective disease progression(n ¼ 18), PSA progression (n ¼ 12), voluntary withdrawal(n ¼ 11), and other (n ¼ 1).

Phase I: dose escalation and DLTsDuring dose escalation, there were no DLTs and an MTD

was not established; however, at 600 mg twice a day, 3 of 5patients experienced severe non-dose-limiting (grade 3)fatigue. All 3 patients were ages�80 years, and consequent-ly, patients�80 years were excluded from the 600 mg twicea day plus prednisone cohort in the phase II portion. Forphase II, prednisone 5 mg twice a day was added to the 400or 600 mg twice a day dose regimens. The decision to notfurther test steroid-free dosing at those levels was based onACTH and associated endocrine data which indicatedincreased risk for mineralocorticoid excess, as well as symp-toms such as fatigue that may have been associated with(delayed) adrenal adaptation to 17a-hydroxylase inhibi-tion. Other phase II cohorts were 300 mg twice a day (n ¼23), 600mg every day (n¼ 24), and 400mg twice a day plusprednisone (n ¼ 24).

SafetyIn phase I, all patients experienced �1 treatment-emer-

gent adverse event (TEAE) and 96% drug-related TEAEs(Table 2). In phase II, all but 1 patient had a TEAE; mostcommon were fatigue (77%), nausea (47%), constipation(37%), and diarrhea (35%). Grade �3 adverse events wereexperienced by 51 patients (53%); most common were

fatigue (12%), hypokalemia (8%), hyperglycemia (5%),and diarrhea (4%). Drug-related adverse events werereported in 97% of patients (Table 2). Two grade 3 hepatictransaminase "investigations" adverse events were reported(per NCI-CTCAE); however, there were no patient discon-tinuations related to hepatic abnormalities.

Serious adverse events (SAE) were experienced by 8(31%) and26 (27%)patients in phases I and2, respectively,andwere drug related in 5 and 7 patients. Drug-related SAEsin phase I were hypertension, nausea, vomiting, deep veinthrombosis (DVT), fatigue, increased amylase, increasedlipase, diarrhea, skin infection, and dehydration (each n¼ 1); in patients receiving orteronel 400mg twice a day plusprednisone, one drug-related SAEof vomitingwas reported.SAEs related to single-agent orteronel in phase II werefatigue (n ¼ 1) and hypertension (n ¼ 1); in patientsreceiving orteronel plus prednisone, drug-related SAEs ofacute renal failure, hypokalemia (each n ¼ 2), pneumonia,decreased hemoglobin, hyperglycemia, hyperkalemia, painin extremity, sensory neuropathy, and DVT (each n ¼ 1)were reported.

As described above, although significant fatigue occurredin older patients receiving 600 mg twice a day withoutprednisone, overall there was no overt evidence of clinicalACTH-adrenal insufficiency in the phase I patients receivingsteroid-free dose regimens. This is presumably due com-pensatory ACTH-driven increased levels of mineralocorti-coids with intrinsic glucocorticoid activity, predominantlycorticosterone.

There were 3 on-study deaths all in the phase II portion;all deaths were considered unrelated to study drug: cardiac-related events (n¼ 2, 600mg every day) and infection (400mg twice a day plus prednisone).

Figure 1. Mean plasma orteronelconcentrations (phase I)following the morning dose oforteronel on day 8 of cycle 1. BID,twice daily.






PharmacokineticsMean orteronel plasma concentrations in cycle 1, day 8

(phase I) following the morning dose are shown in Fig. 1.Pharmacokinetic analysis indicates dose-related increasesin single- and multiple-dose Cmax and AUC0–8 h over the100 to 600mg twice a day dose range. Fasting at the time ofdosing was not required.

Endocrine pharmacodynamicsPharmacodynamic analysis in phase I patients showed

androgen suppression. DHEA-S levels decreased to belowquantifiable levels (assays sensitive to 15 mg/dL) in allpatients receiving orteronel �300 mg twice a day. Testos-terone levels decreased to <10 ng/dL in all patients receivingorteronel �300 mg twice a day (local laboratory assayssensitive to 10 ng/dL).

In phase II, androgen suppression occurred by cycle 1, day15, and responsesweremaximalbycycle2,day1.At12weeks,substantial mean reductions in testosterone [�7.5 ng/dL (SD¼ 5.14)] and DHEA-S [�45.3 mg/dL (SD: 40.26)] wereobserved from baseline (Fig. 2). At 12 weeks, 46% of patients(45 of 97) achieved testosterone <1 ng/dL and 54% and 32%of patients had DHEA-S levels <10 mg/dL or <1 mg/dL,respectively. The most profound reductions occurred in the400mg and 600mg twice a day plus prednisone dose groups.

For phase II, the ACTH-adrenal axis was evaluated usingmeasurements of ACTH, cortisol, and corticosterone. Thenormal range forACTH is 9 to52pg/mL (20) and inpatientsreceiving orteronel 400 mg and 600 mg twice a day plusprednisone, the ACTH-adrenal axis was effectively sup-pressed, with ACTH and cortisol levels reduced relative tobaseline (Fig. 2). In the 300 mg twice a day dose group,mean ACTH levels increased post baseline combined withmodest decreases in cortisol (baseline: 11–15mg/dL; cycle 4:3–10 mg/dL) and increased corticosterone.

Clinical responseIn phase I, orteronel �300 mg was associated with

decreases in PSA levels. Overall, 13 of 20 evaluable patients(65%) had �50% decreases in PSA at 12 weeks.

At 12 weeks, PSA was evaluable in 84 phase II patients(Fig. 3A). Forty-five of 84 evaluable patients (54%) had�50% decline in PSA from baseline and 18 (21%) had�90% decline in PSA. At 24 weeks, a �50% decrease inPSA occurred in 37 of 59 evaluable patients (63%) and17 (29%) of the 59 evaluable patients who remained onstudy treatment had �90% decline in PSA (Fig. 3B).Time to PSA progression is shown in Fig. 3C; theKaplan–Meier estimated median was >225 days in all4 dose groups.

Figure 2. Effect of orteronel on A, testosterone; B, DHEA-S; C, ACTH; and D, corticosterone levels (phase II). QD, once daily.

Dreicer et al.





Prior adrenal-directed therapy (predominantly keto-conazole; abiraterone acetate in 4 patients) seemed tobe associated with a lower likelihood of a obtaining a�50% decrease in PSA at 12 weeks, with only 12 of 33patients (36%) with prior adrenal-directed therapyreaching this threshold, compared with 46 of 71

(65%) who had not received prior adrenal-directedtherapy.

Fifty-one of 97 phase II patients (53%) had RECIST-evaluable radiographic lesions. Unconfirmed RECIST par-tial responses were observed in 10 of 51 evaluablepatients (20%; Table 3), and 21 (41%) had stable disease.

Figure 3. Percent change inPSAat A, 12weeks, andB, 24weeksby dosegroup andprior ketoconazole therapy (phase II), andC, phase II Kaplan–Meier plot fortime to PSA progression. BID, twice daily; QD, once daily.






Radiographic disease progression was reported in 16patients.

CTC analysesAt baseline, themean overall CTC count was 16.6/7.5mL

whole blood (SD ¼ 33.2) among 88 evaluable patients. By12 weeks, mean overall CTC counts had decreased to 3.9/7.5mL (SD¼ 11.2) and themean change in CTCs (baselineto week 12) was �76.5%.

Of 63 patients with evaluable CTC counts at both base-line and 12 weeks, 14 (22%) converted to a favorable CTCcount and36 (57%) retained aCTC count of <5 at 12weeks.

DiscussionFindings of this clinical study demonstrate for the first

time that selective inhibition of 17,20-lyase with orteronelwith/without prednisone, and given without food require-ment, results in PSA and radiographic responses withdeclines in CTCs in men with mCRPC. Pharmacokineticdata demonstrate a dose-dependent relationship that isstable over time. Although the study was not powered tocompare doses, the 2 higher phase II doses with prednisonewere most effective in lowering testosterone and DHEA-Slevels. ACTH and corticosterone levels were modestlyincreased in the steroid-free regimens while relatively sup-pressed in the prednisone-supplemented groups. A moredetailed analysis of the orteronel endocrine profile has beenreported (21).

Orteronelwas generallywell toleratedwith adverse eventsthat were predictable based upon the proposed mechanismof action and co-administration with prednisone; themedi-an orteronel treatment duration of 7 to 9 months is con-sistent with the overall pattern of maintained disease sta-bility combinedwith adequate toleration. Grade�3 adverseeventswere experiencedby 51phase II patients (53%);mostcommon were fatigue, hypokalemia, diarrhea, and hyper-glycemia. No DLTs were observed during phase I. However,severe fatigue (grade 3) occurred in 3 older patients treatedwith 600mg twice a daywithout prednisone. Isolated eventsof prolonged QT-interval were reported, but there was no

relationship to orteronel dose or concentrations and overallacross groups there were no directional changes in any ECGinterval parameters. The absence of a dose response for theobserved common adverse events in this study makes itdifficult to judge their specific relationship to orteroneladministration.

The phase I dose escalation data, combined with thephase II endocrine data, measured using more sensitiveassays, together support that orteronel has selectivity for17,20-lyase versus 17a-hydroxylase. At 300 mg twice a day,orteronel reduced testosterone concentrations by �90% inmost patients, without clinically relevant inhibition of theACTH-cortisol axis. At higher doses, some evidence of 17a-hydroxylase inhibitionwas apparent. In phase I, however, itis not clear whether the severe fatigue observed in patients�80 years receiving 600 mg twice a day was because ofdelayed adaptation to 17a-hydroxylase inhibition or ratherthe effects of acute more profound androgen withdrawal.Less fatigue was noted in subsequent patients receivingeither 400 mg or 600 mg twice a day plus prednisone co-administration. However, there is no compelling evidenceto support the exclusion of men �80 years from therapywith orteronel.

Based on the overall phase I and phase II results, 400 mgtwice a day plus prednisone 5 mg twice a day was the doseregimen taken forward for phase III evaluation in bothpatients with chemotherapy-na€�ve (NCT01193244) andpost-docetaxel (NCT01193257) mCRPC. Furthermore, asprednisone is known to have antitumor activity (22), it wasthought that the addition of prednisone might further thebenefit of orteronel for men with mCRPC.

Phase III patientswho received total doses of 600mgdaily(300 mg twice a day or 600 mg every day) did not receiveconcomitant prednisone. Patients receiving this steroid-freeregimenhad similarPSA responses and radiographic stabilityversus those on the higher-dose regimens. The incidence ofhypokalemia and hypertension was modestly increased inthese2groups relative to400mg twice adayplusprednisone,but overall, the steroid-free regimenswere well tolerated anddid not have higher discontinuation rates. The favorable

Table 3. Objective disease response by RECIST (phase IIa)

Orteronel alone (steroid-free) Orteronel plus prednisone

Patients, n (%)300 mg twicea day

600 mgevery day

400 mg twice a dayplus prednisone

600 mg twice a dayplus prednisone Overall

Best response by RECISTEvaluable patients n ¼ 12 n ¼ 12 n ¼ 10 n ¼ 17 N ¼ 51Complete response 0 0 0 0 0PR 4 (33) 2 (17) 2 (20) 2 (12) 10 (20)SD 4 (33) 5 (42) 6 (60) 6 (35) 21 (41)PR or SD 8 (67) 7 (58) 8 (80) 8 (47) 31 (61)Progressive disease 4 (33) 4 (33) 1 (10) 7 (41) 16 (31)

Abbreviations: PR, partial response; SD, stable disease.aPhase I patients treated at the same dose levels as phase II are included in this analysis.

Dreicer et al.





results in patients receiving orteronel doses of 600 mg dailysuggest that this agent may allow for effective androgensynthesis inhibition without glucocorticoid supplementa-tion. This could be of particular benefit in patients receivingorteronel for prolonged periods or in those at increased riskfrom the effects of prednisone administration because ofcomorbidities such as diabetes or bone loss. The steroid-freeregimen of orteronel 300 mg twice a day is undergoingfurther evaluation in patients with progressive (rising PSA)non-mCRPC (M0; ref. 23), as well as phase III studies inearlier stages of disease (NCT01546987,NCT01707966, andNCT01809691).During the past decade, significant progress in under-

standing the biology of the androgen receptor has beentranslated into clinically relevant therapeutic develop-ments. Two recently approved agents—the steroidalCYP17A1 inhibitor abiraterone acetate and the androgenreceptor inhibitor enzalutamide—have both demonstratedsurvival benefits over placebo in patients withmCRPCpost-docetaxel [14.8 months vs. 10.9 months (11) and 18.4months vs. 13.6 months (24), respectively]. In this new,era of more intensive androgen synthesis inhibitors andandrogen receptor–directed therapies, the optimal timing,sequencing, pharmacoeconomics, ease of administration,and therapy-related toxicity (e.g., effects of or requirementfor co-administered steroids and the timing of any subse-quent chemotherapy) will likely drive decision making inthis clinical setting.

Disclosure of Potential Conflicts of InterestR. Dreicer is a consultant/advisory board member of Millenium, Endo

Pharmaceuticals, Janssen, Dendreon, and Medivation. A. Suri is Director ofClinical Pharmacology in Takeda. W.M. Stadler has a commercial researchgrant from Takeda. G.R. MacVicar has Honoraria from Speakers Bureau ofJanssen Pharmaceuticals and also is a consultant/advisory board member ofMedivation. O. Hamid has other commercial research support fromTakeda—To The Angeles Clinic and Research Institute funding. Y. Shiis Director of Takeda Boston. D.B. Agus is a consultant/advisory boardmember of Takeda Pharmaceuticals. No potential conflicts of interestwere disclosed by the other authors.

DisclaimerEmployees of Takeda Pharmaceuticals International Company partic-

ipated in trial design, data collection, data analysis, data interpretation,and writing of the report. The sponsor of the study was involved in thedesign of the trial and provided grants to trial sites and had no otherinvolvement in conduct of trial. The corresponding author had full accessto all the data in the study and had final responsibility for the decision tosubmit for publication.

Authors' ContributionsConception and design: R. Dreicer, D. MacLean, A. Suri, D.B. AgusDevelopment of methodology: D. MacLean, A. Suri, D.B. AgusAcquisitionofdata (provided animals, acquired andmanagedpatients,provided facilities, etc.): R. Dreicer, D. MacLean, W.M. Stadler, D. Shevrin,L. Hart, G.R. MacVicar, O. Hamid, M.E. Gross, D.B. AgusAnalysis and interpretation of data (e.g., statistical analysis, biosta-tistics, computational analysis): R. Dreicer, D. MacLean, A. Suri, G.R.MacVicar, O. Hamid, J. Hainsworth, M.E. Gross, Y. Shi, D.B. AgusWriting, review, and/or revision of the manuscript: R. Dreicer, D.MacLean, A. Suri, W.M. Stadler, D. Shevrin, L. Hart, G.R. MacVicar, O.Hamid, J. Hainsworth, M.E. Gross, Y. Shi, I.J. Webb, D.B. AgusAdministrative, technical, or material support (i.e., reporting or orga-nizing data, constructing databases): Y. ShiStudy supervision:R.Dreicer, D.MacLean,W.M. Stadler, G.R.MacVicar, O.Hamid, J. Hainsworth, D.B. Agus

AcknowledgmentsThe authors thank the patients who participated in this study and their

families, as well as staff at all investigational sites. They also thank thecontributions of J. Wang and L. DeLeon of Takeda Pharmaceuticals Inter-national Company for statistical and trial management support. The authorsalso thank the editing assistance of C. Crookes of FireKite, Ltd., during thedevelopment of this article, which was funded by Millennium: The TakedaOncology Company.

Grant SupportAll study sites and institutions received funding from Millennium:

The Takeda Oncology Company, Cambridge, MA, to cover the expensesof the investigators, subinvestigators, and study staff for clinical trialexecution.

The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby markedadvertisement in accordance with 18 U.S.C. Section 1734 solely to indicatethis fact.

Received September 9, 2013; revised October 31, 2013; acceptedNovember 19, 2013; published OnlineFirst January 13, 2014.

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2014;20:1335-1344. Published OnlineFirst January 13, 2014.Clin Cancer Res Robert Dreicer, David MacLean, Ajit Suri, et al. Castration-Resistant Prostate Cancer

in Patients with Metastatic−−17,20-Lyase Inhibitor an Investigational−−Phase I/II Trial of Orteronel (TAK-700)

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