V O L U M E 2 6 䡠 N U M B E R 2 8 䡠 O C T O B E R 1 2 0 0 8
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`From the Royal Marsden NHS Founda-
`tion Trust; and The Institute of Cancer
`Research, Sutton, Surrey, United King-
`dom; and Cougar Biotechnology, Los
`Angeles, CA.
`
`Submitted December 28, 2007;
`accepted May 14, 2008; published
`online ahead of print at www.jco.org on
`July 21, 2008.
`
`Supported by Cougar Biotechnology;
`the Section of Medicine is supported
`by a program grant from Cancer
`Research UK, who also fund the Centre
`for Cancer Therapeutics, where the
`pharmacokinetic studies were
`conducted. The authors were also
`supported by the Medical Reserach
`Council, the Prostate Cancer Research
`Foundation, the Royal Marsden Hospital
`Research Fund, an Experimental Cancer
`Medicine Centre grant, and the Bob
`Champion Cancer Trust.
`
`Authors’ disclosures of potential con-
`flicts of interest and author contribu-
`tions are found at the end of this
`article.
`
`Corresponding author: Johann S. de
`Bono, MB ChB, FRCP, MSc, PhD,
`Section of Medicine, The Institute of
`Cancer Research and Drug Develop-
`ment Unit, the Royal Marsden NHS
`Foundation Trust, Downs Rd, Sutton,
`Surrey, United Kingdom SM2 5PT;
`e-mail: johann.de-bono@icr.ac.uk.
`
`© 2008 by American Society of Clinical
`Oncology
`
`0732-183X/08/2628-4563/$20.00
`
`DOI: 10.1200/JCO.2007.15.9749
`
`Phase I Clinical Trial of a Selective Inhibitor of CYP17,
`Abiraterone Acetate, Confirms That Castration-Resistant
`Prostate Cancer Commonly Remains Hormone Driven
`Gerhardt Attard, Alison H.M. Reid, Timothy A. Yap, Florence Raynaud, Mitch Dowsett, Sarah Settatree,
`Mary Barrett, Christopher Parker, Vanessa Martins, Elizabeth Folkerd, Jeremy Clark, Colin S. Cooper,
`Stan B. Kaye, David Dearnaley, Gloria Lee, and Johann S. de Bono
`
`A
`
`B
`
`S
`
`T
`
`R
`
`A
`
`C
`
`T
`
`Purpose
`Studies indicate that castration-resistant prostate cancer (CRPC) remains driven by ligand-
`dependent androgen receptor (AR) signaling. To evaluate this, a trial of abiraterone acetate—a
`potent, selective, small-molecule inhibitor of cytochrome P (CYP) 17, a key enzyme in androgen
`synthesis—was pursued.
`
`Patients and Methods
`Chemotherapy-naı¨ve men (n ⫽ 21) who had prostate cancer that was resistant to multiple
`hormonal therapies were treated in this phase I study of once-daily, continuous abiraterone
`acetate, which escalated through five doses (250 to 2,000 mg) in three-patient cohorts.
`
`Results
`Abiraterone acetate was well tolerated. The anticipated toxicities attributable to a syndrome
`of secondary mineralocorticoid excess—namely hypertension, hypokalemia, and lower-limb
`edema—were successfully managed with a mineralocorticoid receptor antagonist. Antitumor
`activity was observed at all doses; however, because of a plateau in pharmacodynamic effect,
`1,000 mg was selected for cohort expansion (n ⫽ 9). Abiraterone acetate administration was
`associated with increased levels of adrenocorticotropic hormone and steroids upstream of CYP17
`and with suppression of serum testosterone, downstream androgenic steroids, and estradiol in all
`patients. Declines in prostate-specific antigen ⱖ 30%, 50%, and 90% were observed in 14 (66%),
`12 (57%), and 6 (29%) patients, respectively, and lasted between 69 to ⱖ 578 days. Radiologic
`regression, normalization of lactate dehydrogenase, and improved symptoms with a reduction in
`analgesic use were documented.
`
`Conclusion
`CYP17 blockade by abiraterone acetate is safe and has significant antitumor activity in CRPC.
`These data confirm that CRPC commonly remains dependent on ligand-activated AR signaling.
`
`J Clin Oncol 26:4563-4571. © 2008 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`Prostate cancer is the second leading cause of cancer
`death in men in the western world1,2; this is a result
`of castration-resistant prostate cancer (CRPC).3
`Castration blocks gonadal testosterone generation,
`but androgens from nongonadal sources are postu-
`lated to drive androgen receptor (AR) signaling.
`This is supported by recent studies, which report
`high intratumoral androgens, continued AR signal-
`ing,4 and overexpression of enzymes key to andro-
`gen synthesis, which suggests that CRPC may
`synthesize androgens de novo.5-7 Despite this, cur-
`
`rently available strategies that target the AR, such as
`antiandrogens, ketoconazole, estrogens, or glu-
`cocorticoids, result in modest benefit.8-13
`Cytochrome P (CYP)17 is a microsomal en-
`zyme that catalyzes two independently regulated ste-
`roid reactions key to androgen and estrogen
`biosynthesis (Fig 1A).14-16 Congenital CYP17 defi-
`ciency does not result in adrenocortical insuffi-
`ciency, as corticosterone synthesis is unaffected;
`CYP17 loss interrupts the negative feedback control
`of adrenocorticotropic hormone (ACTH), which
`results in high levels of ACTH and steroid precur-
`sors upstream of CYP17.17 Abiraterone is a potent,
`
`© 2008 by American Society of Clinical Oncology
`
`
`Downloaded from jco.ascopubs.org on July 25, 2014. For personal use only. No other uses without permission.Downloaded from jco.ascopubs.org on July 25, 2014. For personal use only. No other uses without permission.Downloaded from jco.ascopubs.org on July 25, 2014. For personal use only. No other uses without permission.
`
`
`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.Copyright © 2008 American Society of Clinical Oncology. All rights reserved.Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
`4563
`
`JANSSEN EXHIBIT 2014
`Mylan v. Janssen IPR2016-01332
`
`

`

`A
`
`ACTH
`
`Attard et al
`
`Pregnenolone
`
`Deoxycorticosterone
`
`Corticosterone
`
`Aldosterone
`
`CYP17:
`17α-hydroxylase
`
`17OH-Pregnenolone
`
`11-deoxycortisol
`
`Cortisol
`
`CY17:
`C17,20-lyase
`
`DHEA
`
`Androstenedione
`
`Testosterone
`
`Estradiol
`
`B
`
`ACTH
`
`× 5
`
`Positive drive
`
`Hypokalemia
`
`Hypertension
`
`Fluid overload
`
`Suppression of Renin
`
`Negative feedback
`
`Pregnenolone
`
`Deoxycorticosterone
`
`× 10
`
`Corticosterone
`
`× 40
`
`Aldosterone
`
`× 1.5
`
`CYP17:
`17α-hydroxylase
`
`17OH-Pregnenolone
`
`11-deoxycortisol
`
`× 4
`
`Cortisol
`
`× 2
`
`CY17:
`C17,20-lyase
`
`DHEA
`
`× 3
`
`Androstenedione
`
`< 2
`ng/dL
`
`Testosterone
`
`< 1 ng/dl
`
`Estradiol
`
`< 80 pg/dl
`
`C
`
`ACTH
`
`× 3
`
`Pregnenolone
`
`Deoxycorticosterone
`
`< 5
`ng/dL
`
`Corticosterone
`
`× 2
`
`Aldosterone
`
`CYP17:
`17α-hydroxylase
`
`17OH-Pregnenolone
`
`11-deoxycortisol
`
`× 2
`
`Cortisol
`
`× 2
`
`CY17:
`C17,20-lyase
`
`DHEA
`
`× 3
`
`Androstenedione
`
`< 2
`ng/dL
`
`Testosterone
`
`< 1 ng/dL
`
`Estradiol
`
`< 80 pg/dL
`
`Fig 1. Physiologic consequences of treat-
`ment with abiraterone acetate. (A) Steroid
`biosynthesis pathway. (B) Abiraterone inhibits
`17␣-hydroxylase (crossed out in red), which
`results in a reduction in serum cortisol and
`a consequent increase in adrenocortico-
`tropic hormone (ACTH) that drives the
`steroid biosynthesis pathway: levels of
`deoxycorticosterone and corticosterone
`increase by a median of 10- and 40-fold,
`respectively. Up to a four-fold incre-
`ase in 11-deoxycortisol is observed, but
`there is complete inhibition of C17,20-
`lyase (crossed out in red) and significant
`suppression of dehydroepiandrostenedi-
`one (DHEA), androstenedione, and tes-
`tosterone. (C) Addition of dexamethasone
`0.5 mg/d to abiraterone acetate results in
`suppression of ACTH to three-fold less than
`baseline levels, a consequent decrease in
`deoxycorticosterone levels to less than the
`limit of sensitivity of the assay used (⬍ 5
`ng/dL), and a consequent decrease in corti-
`costerone levels by two-fold. Similarly, 11-
`deoxycortisol levels decrease. Downstream
`steroid levels remain suppressed.
`
`selective, and irreversible inhibitor of CYP17 (IC50, 2 to 4 nmol/
`L),18-20 unlike the antifungal ketoconazole, which is a less potent and
`competitive inhibitor of several CYP enzymes.21-24 In preclinical tox-
`icology studies, it reduced the weights of androgen dependent organs
`and had minimal side effects in other organs.25 When administered as
`abiraterone acetate, it has good oral bioavailability. First-in-man stud-
`ies reported that abiraterone acetate was safe when administered daily
`for 12 days to men with prostate cancer, and it suppressed testosterone
`synthesis in noncastrate patients.26 We conducted a phase I study to
`define the safety, tolerability, and recommended phase II dose of
`
`abiraterone acetate when administered once daily to castrate men
`with CRPC.
`
`PATIENTS AND METHODS
`
`Patients
`This was a single-center study conducted at the Royal Marsden Hospital
`(RMH), United Kingdom. Castrate patients who had an Eastern Cooperative
`Oncology Group performance status of 0 to 1, a histologic diagnosis of prostate
`
`4564
`
`JOURNAL OF CLINICAL ONCOLOGY
`© 2008 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on July 25, 2014. For personal use only. No other uses without permission.
`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
`

`

`Phase I Trial of Abiraterone Acetate
`
`Table 1. Patient Characteristics
`
`PSA Doubling
`Time Prior to
`Study Entry
`
`Months Days
`
`Presence
`of
`Measurable
`Disease on
`Baseline CT
`Scan
`
`Presence
`of Bone
`Metastasis
`on
`Baseline
`Bone Scan
`
`ERG Gene
`Class
`
`Baseline
`DHEA
`(ng/dL)
`
`Baseline
`Androstenedione
`(ng/dL)
`
`Confirmed
`PSA
`Decline
`(%)†
`
`Duration
`of PSA
`Decline
`(days)
`
`Patient
`No.
`
`Dose
`(mg)
`
`Age
`(years)
`
`Gleason
`Score at
`Diagnosis
`
`Previous
`Systemic
`Treatmentsⴱ
`
`Baseline
`PSA
`(ng/mL)
`
`01
`02
`03
`04
`
`05
`06
`07
`08
`09
`10
`
`11
`12
`
`13
`14
`15
`16
`17
`18
`19
`20
`21
`
`250
`250
`250
`500
`
`500
`500
`750
`750
`750
`1,000
`
`1,000
`1,000
`
`2,000
`2,000
`2,000
`1,000
`1,000
`1,000
`1,000
`1,000
`1,000
`
`52
`66
`68
`72
`
`77
`58
`74
`69
`85
`62
`
`69
`75
`
`60
`82
`62
`62
`78
`72
`72
`62
`67
`
`4 ⫹ 5
`4 ⫹ 5
`3 ⫹ 4
`3 ⫹ 3
`
`N/A
`4 ⫹ 4
`4 ⫹ 5
`N/A
`4 ⫹ 4
`4 ⫹ 4
`
`3 ⫹ 3
`3 ⫹ 4
`
`3 ⫹ 4
`3 ⫹ 3
`4 ⫹ 5
`3 ⫹ 4
`5 ⫹ 3
`5 ⫹ 4
`5 ⫹ 3
`3 ⫹ 5
`3 ⫹ 3
`
`Dex, DES
`HDACi‡
`—
`Dex, DES,
`antiangiogenic,
`and
`pan-CDKi‡
`Dex
`Dex, DES
`—
`—
`Dex, DES
`Dex, DES,
`HDACi‡
`—
`Dex, DES,
`pamidronate
`Dex
`Dex
`
`—
`
`DES
`Dex, DES
`panERBi‡
`—
`—
`
`DES
`
`34.2
`75
`8.8
`354
`
`79
`290
`28.1
`36.8
`46
`110
`
`34.3
`58
`
`39.3
`56
`35.5
`75
`279
`34.6
`30.2
`28.4
`205
`
`0.5
`1.7
`3.7
`2.2
`
`1.6
`2.2
`2.5
`2.6
`2.4
`12.3
`
`11.6
`5.5
`
`2
`5.5
`22.7
`1.1
`0.6
`3
`3.5
`0.7
`1.3
`
`16
`53
`112
`66
`
`49
`67
`75
`78
`73
`375
`
`354
`166
`
`61
`166
`81
`34
`19
`91
`108
`20
`41
`
`No
`No
`Yes
`Yes
`
`Yes
`Yes
`None
`None
`Yes
`No
`
`Yes
`No
`
`No
`Yes
`Yes
`No
`No
`No
`No
`No
`No
`
`Yes
`Yes
`No
`No
`
`Yes
`No
`Yes
`Yes
`Yes
`Yes
`
`Yes
`Yes
`
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`No
`Yes
`Yes
`
`2N
`Edel
`Esplit
`Edel
`
`N/A
`Edel¶
`2N¶
`Edel¶
`2N
`N/A
`
`2N
`2N
`
`2N¶
`N/A
`3N¶
`2N
`2N
`2N¶
`2N
`2N
`2 ⫹ Esplit¶
`
`67
`172
`407
`221
`
`285
`466
`437
`70
`192
`524
`
`320
`320
`
`122
`227
`102
`87
`93
`285
`902
`1310
`320
`
`⬍ 2
`13
`77
`32
`
`46
`23
`52
`16
`46
`70
`
`27
`43
`
`15
`34
`9
`8
`19
`51
`125
`107
`50
`
`No
`ⱖ 90
`ⱖ 90
`ⱖ 75
`
`ⱖ 90
`No
`No
`ⱖ 90
`ⱖ 90
`ⱖ 50
`
`ⱖ 90
`No
`
`ⱖ 75
`No储
`No
`No (ⱖ 30)
`No
`ⱖ 50
`ⱖ 75
`ⱖ 50储
`No (ⱖ 30)储
`
`—
`206
`578§
`421
`
`427
`—
`—
`451§
`465§
`69
`
`406§
`—
`
`351§
`—
`—
`—
`—
`70
`145
`84
`—
`
`Abbreviations: PSA, prostate-specific antigen; CT, computed tomography; DHEA, dehydroepiandrostenedione; Dex, dexamethasone 0.5 mg daily; DES,
`diethylstilboestrol 1 mg/3 mg daily; HDACi, histone deacetylase inhibitor; pan-CDKi, pan– cyclin-dependent kinase inhibitor; N/A, not assessable; N, normal,
`characterized by twinned red (3’-ERG) and green (5’-ERG) FISH signals; panERBi, pan-ERB inhibitor.
`ⴱAll patients were castrate, and all patients had previously progressed on an antiandrogen therapy.
`†Evaluation of decline ⱖ 50%; response of no indicates ⱖ 50% decline was not achieved, and ⱖ 30% decline is noted additionally.
`‡Experimental agents were administered in the context of a clinical trial.
`储A ⱖ 50% decline in PSA occurred on addition of dexamethasone 0.5 mg/day.
`¶ERG gene status confirmed on castration-resistant prostate cancer sample.
`§PSA and clinical responses continue.
`
`adenocarcinoma, and progressive disease as defined by Prostate-Specific
`Antigen Working Group (PSAWG) criteria27 were eligible. Patients were re-
`quired to have a minimum washout period of 4 weeks after the use of prostate
`cancer therapy, except gonadotropin-releasing hormone agonists, and 6 weeks
`after stopping antiandrogens. Patients who had previously received chemo-
`therapy or a radionuclide for their prostate cancer were excluded. Other
`eligibility criteria included normal serum potassium and adequate bone mar-
`row, renal, and hepatic function. Patients were excluded if they had brain
`metastases or spinal cord compression, active autoimmune disease that re-
`quired corticosteroid therapy, uncontrolled hypertension, a history of cardiac
`failure class III or IV, or a serious concurrent medical illness. The study was
`approved by the ethics review committees of the RMH, United Kingdom.
`Study Design
`This was an open-label, dose-escalation study. Capsules of abiraterone
`acetate powder 250 mg were administered once daily, continuously, in 28-day
`cycles, to fasted patients in three-patient cohorts that escalated through the
`preplanned doses of 250, 500, 750, 1,000 and 2,000 mg. Any drug-related grade
`3 or 4 toxicity (excluding nausea, vomiting, or diarrhea controlled by standard
`therapies) that occurred in the first cycle—except the anticipated toxicities
`that related to a syndrome of secondary mineralocorticoid excess, including
`hypertension, hypokalemia, and fluid overload—was considered a dose-
`limiting toxicity (DLT). Toxicity related to elevated mineralocorticoid levels
`
`was managed with a mineralocorticoid receptor antagonist (eplerenone 50 to
`200 mg/d), and treatment of dexamethasone 0.5 mg daily to suppress ACTH
`was only utilized if mineralocorticoid antagonism did not reverse these toxic-
`ities. Spironolactone was not utilized, as it has been reported to bind and
`activate the AR.28 Cohort expansion to six patients was required if one DLT
`was reported. Dose escalation would stop if two DLTs were observed, and the
`preceding cohort would be expanded to six patients. In the absence of any
`DLT, a total of nine patients would be treated to complete food-effect phar-
`macokinetic (PK) studies.
`This study also was prospectively designed to allow the addition of
`dexamethasone (0.5 mg daily) to abiraterone acetate in all patients at disease
`progression to test the hypothesis that resistance could be reversed by sup-
`pressing ACTH and by decreasing upstream androgenic steroids that could
`activate a mutated, promiscuous AR.29,30 We also hypothesized that harboring
`the androgen-dependent TMPRSS2-ERG fusion gene31,32 could indicate de-
`pendence on AR signaling and could define a tumor subgroup with a higher
`response rate to abiraterone acetate.
`Procedures
`Safety evaluations were conducted at baseline, weekly for the first two
`cycles, and at every cycle thereafter. All patients had a physical examination;
`complete blood count; clotting, serum creatinine, electrolyte, and liver func-
`tion tests. An ACTH stimulation test also was performed at baseline. All
`
`www.jco.org
`
`© 2008 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on July 25, 2014. For personal use only. No other uses without permission.
`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
`4565
`
`

`

`Attard et al
`
`adverse events were graded according to the US National Cancer Institute
`common toxicity criteria, version 3.0.
`For the PK analyses of patients who were treated at 250 mg, 500 mg, and
`750 mg, a single dose of abiraterone acetate initially was administered 7 days
`before continuous dosing and after an overnight fast. Venipuncture was car-
`ried out for PK measurements at 1, 2, 4, 6, 8, 24, 48, and 72 hours postdose; on
`days 1, 8, and 15 of cycle 1; and on day 1 of the second and third cycles. Patients
`in the 1,000-mg and 2,000-mg cohorts were randomly assigned to receive two
`single doses of abiraterone acetate (one with high-fat content food, the other
`after an overnight fast) administered 5 days apart on days ⫺7 and ⫺3 before
`continuous dosing. PK analyses after both doses were done at the same
`time points as the lower-dose cohorts. Abiraterone levels were measured by
`liquid chromatography tandem mass spectrometry, using a previously
`published method.33
`Prostate-specific antigen (PSA) was measured at baseline and at the end
`of every cycle. High-resolution computed tomography (CT) scans and bone
`scans were performed on all patients at baseline and every 3 months. Serum
`was collected for the measurement of ACTH, cortisol, deoxycorticosterone
`(DOC), aldosterone, corticosterone, and testosterone at baseline, weekly for
`the first two cycles, and at every cycle thereafter; serum also was collected at
`baseline and at every cycle to measure androstenedione, dehydroepiandro-
`stenedione (DHEA), DHEA sulfate (DHEA-S), and estradiol. Testosterone
`was measured with a supersensitive assay that utilized liquid chromatography
`tandem mass spectrometry (Quest Diagnostics, Lyndhurst, NJ). DHEA-S,
`aldosterone, corticosterone, and DOC were measured by Quest Diagnostics,
`and ACTH, DHEA, androstenedione and estradiol, were measured by the
`RMH Academic Biochemistry Laboratories (London, United Kingdom). Flu-
`orescent in situ hybridization (FISH) that used an ERG break-apart assay34 was
`performed on sections cut from archival tumor tissue, and castration-resistant
`tumors were biopsied for research purposes before or after starting abi-
`raterone acetate.
`
`Data Analyses
`PK was analyzed using a noncompartmental model with WINNonlin
`Software (Model 200; Scientific Consultant, Apex, NC). The food effects were
`assessed by a bioequivalence crossover model. Rates of PSA decline confirmed
`by a second reading were reported as recommended by PSAWG criteria on an
`intention-to-treat basis. CT scans were reported as the best result by Response
`Evaluation Criteria in Solid Tumors (RECIST)35 at least 3 months after the
`start of treatment. For ERG gene status, tumors were classified into one of five
`groups on the basis of the observed FISH patterns, described previously34
`(Appendix Table A1).
`
`RESULTS
`
`Patient Characteristics
`Twenty-one patients (median age, 69 years; range, 52 to 85 years)
`were recruited on to this study between December 13, 2005 and
`February 22, 2007. All patients were resistant to castration and antian-
`drogens. Ten (48%) of 21 patients had previously progressed on
`treatment with continuous steroids; nine (43%) of the 21 had previ-
`ously progressed on diethylstilboestrol; and seven (33%) of these 21
`patients had progressed on treatment with both (Table 1). The median
`baseline PSA was 46 ng/mL (range, 8.8 to 354 ng/mL). At baseline, 17
`(81%) of 21 patients had bone metastasis, and eight (38%) of 21
`patients had soft tissue disease (Table 1). Five patients remain on study
`and have an ongoing clinical response to abiraterone acetate alone;
`seven patients remain on the combination of dexamethasone and
`abiraterone acetate.
`
`Safety and Tolerability
`Dose escalation to the maximum preplanned daily dose of 2,000
`mg was achieved. There were no treatment-related grade 3 or 4 toxic-
`ities in this study. A plateau of endocrine effects was reported at doses
`greater than 750 mg, and 1,000 mg was selected as the dose for phase II
`evaluation. An additional six patients were treated at 1,000 mg to
`complete PK/pharmacodynamic (PD) studies. Hypertension, hypo-
`kalemia, and lower-limb edema were observed in six, 10, and one
`patient, respectively. These side effects were controlled with
`eplerenone. The incidence of hypertension (one of three for 250, 500,
`750, and 1,000 mg, and two of nine for 1,000 mg doses) appears similar
`across all doses (Table 2).
`One patient in the 1,000-mg cohort who had a history of mi-
`graines developed daily grade 2 migrainous headaches after 8 weeks of
`treatment, which necessitated interruption of treatment. Physical ex-
`amination and magnetic resonance imaging of the brain found no
`abnormalities. Serial serum potassium levels were less than 3 mmol/
`dL, which were in keeping with a syndrome of secondary mineralo-
`corticoid excess. Dexamethasone 0.5 mg daily was initiated to
`
`Table 2. Most Common Adverse Events of Abiraterone Acetate by Dose
`
`Event Grade per Dose
`
`Adverse Event
`
`Hypokalemia
`Hypertension
`Peripheral edema
`Headache
`Dyspnea/wheeze (exacerbation of baseline asthma)
`Anorexia
`Fatigue
`Hot flushes
`Testicular atrophy
`ALT/AST increased
`Skin rash
`Dysgeusia
`
`250 mg
`(n ⫽ 3)
`
`1 to 2
`
`0
`1
`0
`0
`0
`0
`0
`1
`0
`0
`0
`1
`
`3
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`500 mg
`(n ⫽ 3)
`
`1 to 2
`
`0
`0
`0
`0
`0
`2
`0
`0
`1
`1
`1
`0
`
`3
`
`1
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`750 mg
`(n ⫽ 3)
`
`1 to 2
`
`2
`1
`0
`0
`0
`0
`1
`1
`0
`0
`0
`0
`
`3
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`1,000 mg
`(n⫽ 9)
`
`1 to 2
`
`5
`2
`0
`1
`1
`0
`1
`1
`0
`0
`0
`0
`
`2,000 mg
`(n ⫽ 3)
`
`1 to 2
`
`2
`2
`1
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`3
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`3
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`4566
`
`JOURNAL OF CLINICAL ONCOLOGY
`© 2008 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on July 25, 2014. For personal use only. No other uses without permission.
`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
`

`

`Phase I Trial of Abiraterone Acetate
`
`suppress ACTH, and the patient’s headaches resolved, which allowed
`the recommencement of abiraterone acetate in combination with
`dexamethasone. The cause of headache in this patient remains un-
`known, but a causal relationship with abiraterone acetate could not be
`excluded. Another patient treated at 1,000 mg who had a history of
`asthma that was controlled on inhaled ␤2 agonists developed an acute
`exacerbation of asthma that was associated with a decline in peak
`expiratory flow rate (PEFR), hypereosinophilia, an increase in inflam-
`matory markers, and a seven-fold increase in PSA 7 weeks after start-
`ing abiraterone acetate. High doses of steroids were initiated. After
`control of the patient’s symptoms, PEFR and eosinopilia normalized,
`and the PSA returned to the pre-exacerbation level. Subsequently, he
`was maintained on a combination of abiraterone acetate and dexa-
`methasone 0.5 mg daily for 22 weeks with no recurrent increase
`in PSA.
`No other adverse effects that required intervention were re-
`ported in this study. Grade 2 fatigue and anorexia were both
`reported in two patients, and three patients complained of grade 1
`hot flushes. A grade 1 increase in liver transaminases was reported
`in one patient; this abnormality resolved without treatment inter-
`ruption (Table 2).
`
`Plasma PK
`Plasma was collected from all 21 patients for PK analysis. Mean
`apparent clearance values ranged from 494.3 to 1,347.2 L/h. The area
`under the concentration-time curve (AUC) and maximum concen-
`tration (Cmax) increased with dose but not proportionally (r2 ⫽ 0.186
`and 0.049, respectively; Figs 2A and 2B). Up to five-fold differences
`were observed in AUC and Cmax within the 250-mg and 500-mg
`cohorts, and 2.5-fold variations were observed at 750-mg and
`2,000-mg cohorts. In the 1,000-mg cohort, the variation reached nine-
`fold. The terminal half-life was relatively consistent (mean, 10.3 hours;
`Fig 2C). When administered with food that had high-fat content, drug
`exposure was significantly increased (by 4.4-fold) compared with fast-
`ing administration (P ⫽ .049; Fig 2D). The variability between fed
`patients was comparable to that observed between fasted patients.
`There was no significant increase in Cmax, but absorption was signifi-
`cantly extended after food.
`
`PD: Endocrine Studies
`Circulating testosterone levels were in the castrate range (me-
`dian, 7 ng/dL; range, ⬍ 1 to 34) at baseline in all patients, and they
`rapidly became undetectable (⬍ 1 ng/dL) within 8 days at all doses
`
`R2 = 0.053
`
`1,800
`
`1,600
`
`1,400
`
`1,200
`
`1,000
`
`800
`
`600
`
`400
`
`200
`
`B
`
`Cmax (nmol/L)
`
`R2 = 0.203
`
`14,000
`
`12,000
`
`10,000
`
`8,000
`
`6,000
`
`4,000
`
`2,000
`
`0
`
`250
`
`500
`
`750
`
`1,000 1,250 1,500 1,750 2,000
`Dose (mg)
`
`0
`
`250
`
`500
`
`750
`
`1,000 1,250 1,500 1,750 2,000
`Dose (mg)
`
`After fasting
`After high-fat meal
`
`0
`
`5
`
`10
`
`15
`
`20
`25
`30
`Time (hours)
`
`35
`
`40
`
`45
`
`50
`
`10
`
`1
`
`0.1
`
`0.01
`
`0.001
`
`D
`
`Plasma Concentration (nmol/L)
`
`3,000
`2,750
`2,500
`2,250
`2,000
`1,750
`1,500
`1,250
`1,000
`750
`500
`250
`
`0
`
`250
`
`500
`
`750
`
`1,000 1,250 1,500 1,750 2,000
`Dose (mg)
`
`A
`
`Area Under the Curve (hr*nmol/L)
`
`C
`
`Apparent Plasma Clearance (CL/F)
`
`Fig 2. Pharmacokinetics of abiraterone acetate. (A) Area under the concentration-time curve versus dose in fasted patients; (B) maximum concentration (Cmax) versus
`dose in fasted patients; (C) apparent plasma clearance (CL/F) in fasted patients at all doses; (D) plasma concentration versus time profile in a patient treated with
`abiraterone acetate 1,000 mg who fasted and received abiraterone acetate after a high-fat meal.
`
`www.jco.org
`
`© 2008 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on July 25, 2014. For personal use only. No other uses without permission.
`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
`4567
`
`

`

`28
`56
`84
`112
`140
`Time After Treatment (days)
`
`500
`
`400
`
`300
`
`200
`
`100
`
`0
`
`Concentration (ng/dL)
`
`Androstenedione
`
`C
`
`15,000
`
`10,000
`
`5,000
`
`F
`
`Concentration (ng/dL)
`
`Corticosterone
`
`Attard et al
`
`28
`56
`84
`112
`140
`Time After Treatment (days)
`
`500
`
`400
`
`300
`
`200
`
`100
`
`0
`
`100
`
`10
`
`0
`
`28
`56
`84
`112
`140
`Time After Treatment (days)
`
`0
`
`250
`
`500
`750
`1,000 2,000
`Dose (mg)
`
`B
`
`DHEA Concentration
`
`(ng/dL)
`
`Concentration (ng/dL)log 10
`
`Deoxycorticosterone
`
`28
`56
`84
`112
`140
`Time After Treatment (days)
`
`E
`
`14
`
`7
`
`0
`
`A
`
`Concentration (ng/dL)
`
`Testosterone
`
`D
`
`Corticosterone
`
`Concentration (ng/dL)log 10
`
`10,000
`
`3,162
`
`1,000
`
`316
`
`100
`
`0
`
`28
`56
`84
`112
`140
`Time After Treatment (days)
`
`Fig 3. Pharmacodynamic end points. Treatment with abiraterone acetate results in significant suppression of testosterone, dehydroepiandrostenedione (DHEA), and
`androstenedione. Median levels (error bars represent interquartile ranges) for serum levels of (A) testosterone, (B) androstenedione, and (C) DHEA at baseline and for
`the first 142 days of treatment. Abiraterone was found to cross-react with the DHEA assay used, which may explain the detectable levels of DHEA on abiraterone
`acetate. At every time point on treatment, levels of testosterone and androstenedione in all patients are less than the lower limit of sensitivity of the assay used. Median
`levels (log10 values on y-axis; error bars represent interquartile ranges) for serum levels of (D) corticosterone and (E) deoxycorticosterone at baseline and for the first
`142 days of treatment. Mean values (error bars represent 1SD) of (F) corticosterone at day 28 for every dose level (three patients who received 250 mg; two patients,
`500 mg; three patients, 750 mg; six patients, 1,000 mg; and three patients, 2,000 mg).
`
`tested (Fig 3A). The median value of DHEA at baseline was 282.4
`ng/dL (range, 66 to 1,299 ng/dL), at day 28 was 83.6 ng/dL (range, 60.5
`to 174.6 ng/dL), and at day 56 was 79.2 ng/dL (range, 40.3 to 103.7
`ng/dL; Fig 3B). The median baseline value for androstenedione was
`33.5 ng/dL (range, ⬍ 2 to 124.6 ng/dL); androstenedione was sup-
`pressed to less than 2 ng/dL at day 28 in all patients (Fig 3C; Table 1).
`The median baseline value of DHEA-S was 39 ␮g/dL (range, ⬍ 15 to
`117 ␮g/dL), and nine of 21 patients had undetectable DHEA-S at
`baseline; all patients had undetectable DHEA-S (⬍ 15 ␮g/dL) at day
`28. There was no increase in testosterone, androstenedione, DHEA, or
`DHEA-S levels during treatment, including at PSA or radiologic pro-
`gression. Estradiol was suppressed to less than 80 pg/dL at day 28 in all
`patients (median at baseline, 196 pg/dL; range, 117 to 548 pg/dL).
`At all dose levels, treatment was associated with an up to six-fold
`increase in ACTH levels and increased steroid precursor levels up-
`stream of CYP17, including a median 10-fold (range, four-fold to
`50-fold) increase in DOC and a median 40-fold (range, 10-fold to
`95-fold) increase in corticosterone (Fig 1B). The median corticoste-
`rone level at baseline was 133 ng/dL (range, 31 to 468 ng/dL) and at day
`86 was 6,514 ng/dL (range, 1,390 to 17,921 ng/dL; Fig 3D). The
`median DOC level at baseline was 6.5 ng/dL (range, 2 to 64 ng/dL) and
`at day 86 was 68.5 ng/dL (range, 15 to 176 ng/dL; Fig 3E). The increases
`in corticosterone and DOC increased with dose escalation from 250
`mg to 750 mg before they reached a plateau,and no significant differ-
`ence in levels was observed between patients treated at 750 mg to 2,000
`mg (Fig 3F). Administration of dexamethasone to patients who re-
`
`ceived abiraterone acetate resulted in suppression of ACTH and a
`decrease in upstream steroids to less than baseline levels (Fig 1C).
`
`Antitumor Activity
`Greater than 50% declines in PSA confirmed after 1 month
`that lasted for more than 3 months from the start of treatment were
`observed in 12 (57%) of 21 patients with CRPC. Fourteen (66%) of
`21, nine (42%) of 21, and six (29%) of 21 patients had ⱖ 30%,
`ⱖ 75%, and ⱖ 90% declines in PSA, respectively, which were
`confirmed after 1 month and which lasted for more than 3 months
`from the start of study (lasted between 69 and ⱖ 578 days, and
`censured on September 14, 2007; Table 1). Five (62%) of eight
`patients with measurable disease at baseline had confirmed partial
`responses by RECIST. Radiologic regression of pelvic and para-
`aortic lymphadenopathy was observed in three patients, and re-
`gression of soft-tissue metastasis in the pelvis,
`lungs, and
`mediastinum was observed in two patients (Fig 4). Resolving bone
`disease was observed on CT and bone scan in two patients (Fig 4).
`Eleven patients had pain that required analgesics at baseline, and
`eight of 11 had symptom improvement that allowed a reduction in
`dose or cessation of analgesic use. Seven patients had an increased
`lactate dehydrogenase at baseline that decreased to less than the
`upper limit of normal in five of seven patients.
`
`Reversal of Resistance
`The addition of dexamethasone 0.5 mg/d resulted in successful
`salvage in four of 15 patients who had progressed by PSAWG criteria
`
`4568
`
`JOURNAL OF CLINICAL ONCOLOGY
`© 2008 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on July 25, 2014. For personal use only. No other uses without permission.
`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
`

`

`A1
`
`B1
`
`D1
`
`Phase I Trial of Abiraterone Acetate
`
`A2
`
`A3
`
`B2
`
`C1
`
`C2
`
`D2
`
`Fig 4. Antitumor activity. Patient 2 had a
`vertebral metastasis in T10 on baseline
`computed tomography (CT) scan (A1) that
`was superseded by bone remodeling on
`repeat CT scan 6 months after starting
`abiraterone acetate (A2). These radiologic
`changes were supported by a prostate-
`specific antigen (PSA) decline from 75 to
`5.5 ng/mL, a decrease in alkaline phospha-
`tase (ALP) levels from 357 to 112 U/L, a
`decrease in circulating tumor cell count
`from 12 to one, and complete resolution
`of back pain. This patient’s prostate-
`specific antigen response lasted 206 days.
`Fluorescent in situ hybridization on this
`patient’s archival transrectal biopsy of the
`prostate cores identified a tumor with a
`class Edel ERG rearrangement. (A3) Can-
`cer nuclei with loss of 5⬘-ERG; repre-
`sented in inset. Patient 8 had a decline in
`PSA from 36.8 to 0.98 ng/mL, a partial
`response by Response Evaluation Criteria
`in Solid Tumors (RECIST), and a reduction
`in the size of pelvic and mediastinal lymph
`nodes and lung metastases; panel 2 dem-
`onstrates an anterior lung metastasis that
`measured 13.9 mm at baseline (B1) and
`was reduced in size to 6.2 mm after 6
`months of treatment (B2). This patient’s
`PSA response continued after greater
`than 465 days. Patient 5 had a reduction in
`the intensity of bone metastasis in the
`right sixth rib and L2 vertebra on bone
`scan compared with baseline after 6
`months of treatment (C2) compared with
`baseline (C1). These radiologic changes
`were supported by a decline in PSA from
`76 to 0.53 ng/mL, of ALP from 262 to 77
`U/L, and resolution of pain. Patient 5 pro-
`gressed by PSA working group criteria after
`427 days. Patient 11 had a decline in PSA
`from 34.3 to 0.21 ng/mL and a partial re-
`sponse by RECIST with resolution of pelvic
`lymphadenopathy, which measured 20 mm
`on baseline CT scan (D1) and 4 mm on CT
`scan after 4 months (D2). This response has
`continued after greater than 406 days.
`
`on abiraterone acetate alone (PSA decrements by 36% [patient 10],
`ⱖ 99% [patient 14], 68% [patient 19], and 73% [patient 21] that lasted
`ⱖ 349, ⱖ 265, ⱖ 49, and ⱖ 81 days, respectively; all four patients have
`an ongoing response). Two of these four patients previously had
`progressive disease on the same dose and schedule of single-agent
`dexamethasone (Appendix Fig A1).
`
`ERG Gene Status
`Tumor tissue was available from 18 of 21 patients and included
`matched hormone-sensitive and castration-resistant samples (four
`prostates, one liver metastasis, one para-ureteric tumor) collected
`from six patients. Six patients had an ERG rearrangement (Table 1).
`Five (83%) of six patients with an ERG rearrangement had a ⱖ 50%
`decline in PSA (which included patient 21, who had an initial, short-
`lived ⱖ 30% decline in PSA on abiraterone alone but a ⱖ 50% decline
`in PSA after the addition of low-dose dexamethasone to abiraterone).
`The patien