V O L U M E 2 8 䡠 N U M B E R 9 䡠 M A R C H 2 0 2 0 1 0
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`Phase I Clinical Trial of the CYP17 Inhibitor Abiraterone
`Acetate Demonstrating Clinical Activity in Patients With
`Castration-Resistant Prostate Cancer Who Received Prior
`Ketoconazole Therapy
`Charles J. Ryan, Matthew R. Smith, Lawrence Fong, Jonathan E. Rosenberg, Philip Kantoff, Florence Raynaud,
`Vanessa Martins, Gloria Lee, Thian Kheoh, Jennifer Kim, Arturo Molina, and Eric J. Small
`
`See accompanying editorial on page 1447 and articles on pages 1489 and 1496
`
`A
`
`B
`
`S
`
`T
`
`R
`
`A
`
`C
`
`T
`
`Purpose
`Abiraterone acetate is a prodrug of abiraterone, a selective inhibitor of CYP17, the enzyme catalyst
`for two essential steps in androgen biosynthesis. In castration-resistant prostate cancers (CRPCs),
`extragonadal androgen sources may sustain tumor growth despite a castrate environment. This
`phase I dose-escalation study of abiraterone acetate evaluated safety, pharmacokinetics, and
`effects on steroidogenesis and prostate-specific antigen (PSA) levels in men with CPRC with or
`without prior ketoconazole therapy.
`Patients and Methods
`Thirty-three men with chemotherapy-naïve progressive CRPC were enrolled. Nineteen patients
`(58%) had previously received ketoconazole for CRPC. Bone metastases were present in 70% of
`patients, and visceral involvement was present in 18%. Three patients (9%) had locally advanced
`disease without distant metastases. Fasted or fed cohorts received abiraterone acetate doses of
`250, 500, 750, or 1,000 mg daily. Single-dose pharmacokinetic analyses were performed before
`continuous daily dosing.
`Results
`Adverse events were predominantly grade 1 or 2. No dose-limiting toxicities were observed.
`Hypertension (grade 3, 12%) and hypokalemia (grade 3, 6%; grade 4, 3%) were the most frequent
`serious toxicities and responded to medical management. Confirmed ⱖ 50% PSA declines at
`week 12 were seen in 18 (55%) of 33 patients, including nine (47%) of 19 patients with prior
`ketoconazole therapy and nine (64%) of 14 patients without prior ketoconazole therapy.
`Substantial declines in circulating androgens and increases in mineralocorticoids were seen
`with all doses.
`Conclusion
`Abiraterone acetate was well tolerated and demonstrated activity in CRPC, including in patients
`previously treated with ketoconazole. Continued clinical study is warranted.
`
`J Clin Oncol 28:1481-1488. © 2010 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`Androgen deprivation therapy is the standard of
`care for patients with advanced prostate cancer.
`However, virtually all patients eventually develop
`castration-resistant prostate cancer (CRPC), the le-
`thal form of prostate cancer where less than 20% of
`men survive beyond 3 years.1-3
`Historically, castration-resistant tumors were
`thought to have no reliance on androgen receptor
`(AR) signaling for growth and survival, prompt-
`ing characterization as androgen independent
`
`or hormone resistant. However, recent findings
`suggest that AR signaling persists in many of
`these tumors,4-7 the result of adaptive mecha-
`nisms that permit survival in the castrate-level
`androgen environment.8-10
`Although medical or surgical androgen de-
`privation abrogates gonadal testosterone produ-
`ction, circulating testosterone of up to 10% of
`precastrate levels may persist as a result of androgen
`production from the adrenal glands or the tumor
`itself.10 Through its inhibitory action on the choles-
`terol side-chain cleavage enzyme as well as CYP17,
`
`© 2010 by American Society of Clinical Oncology
`
`1481
`
`From the Urologic Oncology Program,
`University of California, San Francisco;
`Helen Diller Family Comprehensive
`Cancer Center, University of California,
`San Francisco, San Francisco; Cougar
`Biotechnology, Los Angeles, CA;
`Massachusetts General Hospital; Dana-
`Farber Cancer Institute, Lank Center for
`Genitourinary Oncology, Boston, MA;
`and Institute of Cancer Research, Drug
`Metabolism and Pharmacokinetics
`Team, Belmont, Sutton, United King-
`dom.
`
`Submitted May 15, 2009; accepted
`August 21, 2009; published online
`ahead of print at www.jco.org on
`February 16, 2010.
`
`Supported by Cougar Biotechnology,
`the Department of Defense Prostate
`Cancer Clinical Trials Consortium, and
`Grant No. K23CA115775 (C.J.R.) from
`the National Institutes of Health. V.M.
`and F.R. are employees of The Institute
`of Cancer Research, which has a
`commercial interest in the development
`of abiraterone and operates a rewards
`to inventors scheme. The Institute of
`Cancer Research has been involved in a
`commercial collaboration with Cougar
`Biotechnology.
`
`Authors’ disclosures of potential con-
`flicts of interest and author contribu-
`tions are found at the end of this
`article.
`
`Clinical Trials repository link available on
`JCO.org.
`
`Corresponding author: Charles J. Ryan,
`MD, Associate Professor of Clinical
`Medicine, Helen Diller Family Compre-
`hensive Cancer Center, University of
`California, San Francisco, 1600 Divisad-
`ero St, San Francisco, CA 94115;
`e-mail: ryanc@medicine.ucsf.edu.
`
`© 2010 by American Society of Clinical
`Oncology
`
`0732-183X/10/2809-1481/$20.00
`
`DOI: 10.1200/JCO.2009.24.1281
`
`WCK1095
`Wockhardt Bio AG v. Janssen Oncology, Inc.
`IPR2016-01582
`
`1
`
`

`

`Ryan et al
`
`ketoconazole has demonstrated activity as a secondary hormonal
`manipulation in CRPC. In a phase III clinical trial in metastatic CRPC,
`28% of patients treated with ketoconazole experienced a ⱖ 50%
`decline in prostatic-specific antigen (PSA), and the median survival
`time was approximately 16 months. Notably, progression of disease
`on this study was shown to be associated with an increase in adrenal
`androgen levels, indicating a failure of the drug to durably suppress
`hormone production.11
`Abiraterone acetate and its metabolite, abiraterone, are potent
`and selective inhibitors of CYP17 ␣-hydroxylase and C17,20-lyase ac-
`tivities, both essential steps in androgen biosynthesis. In human mi-
`crosomes, the concentration of abiraterone required to produce 50%
`inhibition of CYP17 is approximately 10% that of ketoconazole.12,13
`The current report details findings from a phase I trial of abiraterone
`acetate in men with CRPC both with and without prior ketoconazole
`therapy and provides important insights into the endocrinologic and
`clinical effects of potent CYP17 inhibition.
`
`PATIENTS AND METHODS
`
`Major Eligibility Criteria
`Men with histologically confirmed adenocarcinoma of the prostate and
`disease progression despite androgen deprivation therapy (either a luteinizing
`hormone–releasing hormone agonist or orchiectomy) were eligible. When
`appropriate, progression after antiandrogen withdrawal was required. Patients
`with metastatic disease or PSA-only progression by the PSA Working Group
`criteria14 were eligible. Prior chemotherapy for prostate cancer was not al-
`lowed. Use of other hormonal therapies, systemic corticosteroids, or any other
`product known to decrease PSA levels was not permitted within 4 weeks of
`treatment initiation. Eligibility required an Eastern Cooperative Oncology
`Group performance status of 0 or 1, serum creatinine ⱕ 1.5⫻ the institutional
`upper limit of normal [ULN], bilirubin ⱕ 1. ⫻ ULN, AST and ALT ⱕ 2.5 ⫻
`
`ULN, serum potassium ⱖ 3.5 mmol/L, and baseline adrenocorticotropic
`hormone (ACTH) stimulation test peak cortisol level of more than 18 ␮g/dL.
`Patients with uncontrolled hypertension, New York Heart Association Class
`III or IV congestive heart failure, autoimmune disease requiring corticosteroid
`therapy, or other illness interfering with study participation were ineligible.
`Prior ketoconazole therapy was not required for eligibility for the study.
`
`Study Design and Treatment
`The primary objective of this phase I, dose-escalation trial was determi-
`nation of the maximum-tolerated dose (MTD) of abiraterone acetate admin-
`istered orally on a continuous schedule in men with CRPC with and without
`prior ketoconazole therapy. Endocrine and pharmacokinetic effects were sec-
`ondary objectives. The study was approved by the institutional review boards
`of the participating institutions and was conducted in accordance with the
`ethical principles of the World Medical Association Declaration of Helsinki.
`All patients provided written informed consent.
`Medical maintenance of a castrate testosterone level was required for
`patients without prior orchiectomy. Abiraterone acetate was administered
`orally as a 250-mg tablet in escalating dose cohorts of 250, 500, 750, and 1,000
`mg, with fed and fasted cohorts enrolled at each dose. On day –7, patients were
`administered a single dose of abiraterone acetate for pharmacokinetic analysis
`after an overnight fast or 30 minutes after starting a 800- to 1,000-calorie
`breakfast.15 After 7 days, drug was administered daily.
`Dose-limiting toxicity (DLT) was defined as any drug-related grade ⱖ 3
`toxicity by the Common Terminology Criteria for Adverse Events (version 3)
`observed in the first 28 days. Neither fatigue responding to corticosteroid
`replacement nor grade 3 hypertension manageable with mineralocorticoid
`antagonists or corticosteroids was considered dose limiting. A single DLT
`event would expand a cohort to six patients, two DLT events would de-escalate
`to a lower dose cohort, and more than two DLTs among six patients would
`stop escalation and define the prior dose level as the MTD. Continuation of
`therapy beyond 28 days was allowed at the discretion of the physician.14,15
`Use of a glucocorticoid was allowed for patients with clinical symptoms
`of adrenal insufficiency and fatigue, whereas mineralocorticoid excess could
`receive the aldosterone antagonists. Spironolactone was not permitted because
`of its potential to act as an AR agonist.16
`
`Characteristic
`
`Age, years
`Median
`Range
`ECOG performance status, No. of patients
`0
`1
`PSA, ng/mL
`Median
`Range
`Gleason score, No. of patients
`⬍ 7
`7
`⬎ 7
`Disease involvement, No. of patients
`Elevated PSA
`Prostate
`Lymph node
`Bone
`Viscera
`Prior ketoconazole therapy, No. of patients
`
`Table 1. Patient Demographics and Clinical Characteristics
`
`Abiraterone Acetate Dose
`
`Total Patients
`(N ⫽ 33)
`
`250 mg
`(n ⫽ 6)
`
`72
`56-85
`
`30
`3
`
`33
`7-5,436
`
`5
`13
`15
`
`33
`14
`11
`23
`6
`19
`
`65
`61-76
`
`5
`1
`
`35
`16-98
`
`1
`1
`4
`
`6
`1
`2
`5
`0
`5
`
`500 mg
`(n ⫽ 9)
`
`71
`56-76
`
`9
`0
`
`45
`8-5,436
`
`1
`2
`6
`
`9
`2
`2
`6
`3
`7
`
`750 mg
`(n ⫽ 6)
`
`74
`63-85
`
`6
`0
`
`29
`12-205
`
`0
`4
`2
`
`6
`4
`2
`5
`1
`1
`
`1,000 mg
`(n ⫽ 12)
`
`76
`59-83
`
`10
`2
`
`28
`7-451
`
`3
`6
`3
`
`12
`7
`5
`7
`2
`6
`
`Abbreviations: ECOG, Eastern Cooperative Oncology Group; PSA, prostate-specific antigen.
`
`1482
`
`© 2010 by American Society of Clinical Oncology
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`2
`
`

`

`Phase I Study of Abiraterone in CRPC
`
`Evaluations
`Baseline evaluations included a history, examination, CBC counts and
`serum chemistries, PSA, serum testosterone, assessment of adrenal steroido-
`genesis (ACTH, luteinizing hormone, follicle-stimulating hormone, cortico-
`sterone, cortisol, 11-deoxycorticosterone, 11-deoxycortisol, aldosterone, and
`dehydroepiandrosterone sulfate [DHEA-S]), and imaging studies as clinically
`indicated. Testosterone levels were measured by a commercial assay method
`(liquid chromatography–tandem mass spectrometry, lower limit of quantita-
`tion of 1.0 ng/dL; Quest Diagnostics, Madison, NJ). Evaluations were repeated
`weekly throughout the first cycle of therapy and before day 1 of any subsequent
`cycles. Imaging studies were repeated at cycles 4, 7, and 10, as clinically war-
`ranted. Clinical activity was evaluated using PSA decline parameters according
`to PSA Working Group criteria.14
`
`Pharmacokinetic Analysis
`Blood samples for pharmacokinetic analysis were collected at hours 1, 2,
`4, 8, 12, 24, and 48 after single-dose administration of abiraterone acetate on
`day ⫺7, before dosing on days 1, 8, 15, and 22 of cycle 1, and before the first
`dose of any subsequent cycles. Abiraterone acetate and abiraterone plasma
`concentrations were analyzed by a liquid chromatography–tandem mass spec-
`trometry assay developed and performed by the Institute of Cancer Research
`Drug Metabolism and Pharmacokinetics Team (Belmont, Sutton, United
`Kingdom). The assays were validated and linear within the range of 5 to 500
`nmol/L. Noncompartmental pharmacokinetic analyses were performed using
`WINNonlin (Scientific Consultant, Apex, NC) software. Estimated parame-
`ters included maximum concentration (Cmax), time of maximum observed
`concentration, terminal half-life, total body apparent clearance, apparent vol-
`ume of distribution (Vd), and area under the curve (AUC) from the time of
`dosing to the last measurable concentration (AUClast) and extrapolated to
`infinity (AUC0-⬁).
`
`RESULTS
`
`Patient Characteristics
`Between July 2006 and December 2007, 33 patients with CRPC
`were enrolled (Table 1). Seventy percent had bone metastasis, 18%
`had visceral involvement, and three patients (9%) had locally ad-
`vanced disease without distant metastases. Nineteen patients (58%)
`had received prior ketoconazole therapy for CRPC. The median du-
`ration of ketoconazole therapy was 15 months (range, 1.6 to 42
`months), and 16 (84%) of 19 patients had achieved a ⱖ 50% decline in
`PSA on ketoconazole. The median interval from the date of discontin-
`uation of ketoconazole until beginning therapy with abiraterone was
`7.0 months (range, 1.8 to 31 months). Of the 19 patients, ketoconazole
`had been discontinued in 15 patients (79%) because of disease pro-
`gression and in four patients (21%) because of toxicity.
`
`Dose Escalation
`Tolerability was acceptable through 1,000 mg daily in both
`fasted and fed patients, and no DLTs were observed. The 500-mg
`dose cohort was expanded to include three additional patients
`(total of six patients in the fasted cohort) after one patient treated at
`this dose level experienced a syncopal event that was subsequently
`determined to be unrelated to study therapy. This type of event was
`not observed in subsequent patients. On the basis of evidence
`of clinical responses across several doses, maximization of the
`intended endocrinologic effects, and the favorable safety, dose
`
`Table 2. Incidence of Most Common (⬎ 10%) Adverse Events of Abiraterone Acetate in Patients With Castration-Resistant Prostate Cancer
`
`All Grades
`(N ⫽ 33)
`
`No. of
`Patients
`
`6
`7
`10
`7
`4
`11
`5
`8
`22
`5
`8
`7
`4
`8
`5
`4
`5
`5
`11
`7
`7
`12
`4
`
`%
`
`18
`21
`30
`21
`12
`33
`15
`24
`67
`15
`24
`21
`12
`24
`15
`12
`15
`15
`33
`21
`21
`36
`12
`
`Adverse Event
`
`Abdominal pain
`Constipation
`Diarrhea
`Dry mouth
`Dyspepsia
`Nausea
`Vomiting
`Asthenia
`Fatigue
`Edema
`Peripheral edema
`Anorexia
`Hyperglycemia
`Hypokalemia
`Arthralgia
`Back pain
`Muscular weakness
`Dizziness
`Headache
`Cough
`Hot flush
`Hypertension
`Hypotension
`
`Dose Cohort (No. of patients)
`
`250 mg
`(n ⫽ 6)
`
`500 mg
`(n ⫽ 9)
`
`750
`(n ⫽ 6)
`
`1,000 mg
`(n ⫽ 12)
`
`Grade
`1/2
`
`Grade
`3
`
`Grade
`1/2
`
`1
`
`1
`
`1
`3
`1
`
`1
`1
`
`1
`1
`2
`
`1
`
`2
`1
`
`2
`2
`3
`2
`2
`3
`1
`3
`7
`3
`2
`2
`1
`
`1
`1
`1
`3
`1
`2
`1
`3
`
`Grade
`3/4
`
`1
`
`1
`
`1
`
`Grade
`1/2
`
`Grade
`3
`
`Grade
`1/2
`
`Grade
`3
`
`2
`2
`2
`3
`2
`1
`1
`2
`4
`
`1
`
`3
`2
`1
`1
`2
`2
`4
`2
`2
`
`1
`2
`4
`2
`
`6
`3
`2
`8
`1
`6
`3
`2
`2
`1
`1
`
`2
`6
`1
`3
`3
`
`1
`
`1
`
`1
`
`1
`
`1
`1
`
`2
`
`www.jco.org
`
`© 2010 by American Society of Clinical Oncology
`
`1483
`
`3
`
`

`

`Ryan et al
`
`escalation was ceased at 1,000 mg. These findings paralleled a
`concurrent study with abiraterone acetate.16
`
`Toxicity
`The most common adverse events were fatigue, hypertension,
`headache, nausea, and diarrhea (Table 2). Adverse events were
`predominantly grade 1 or 2. Grade 3 toxicities consisted of hyper-
`tension (n ⫽ 4), hypokalemia (n ⫽ 2), constipation (n ⫽ 1),
`diarrhea (n ⫽ 1), muscular weakness (n ⫽ 1), and arthralgia
`(n ⫽ 1). One patient treated at the 500-mg dose level developed
`grade 4 hypokalemia. The three episodes of grade 3 or 4 hypokale-
`
`mia all occurred after cycle 1. Only one episode of grade 1 hypoka-
`lemia occurred in cycle 1. There was no observed increase in
`toxicity in patients who had previously been treated with ketocon-
`azole. Grade 3 or 4 toxicities occurred in seven (37%) of 19 patients
`with prior ketoconazole exposure and in six (55%) of 11 patients
`without prior ketoconazole exposure.
`
`Endocrine Effects
`As predicted, therapy with abiraterone acetate resulted in a sub-
`stantial reduction of circulating androgen levels and an increase in
`mineralocorticoids such as deoxycorticosterone, upstream of CYP17
`
`Baseline
`(Day -7)
`
`Day 28
`
`20
`18
`16
`14
`12
`10
`
`2468
`
`0
`
`Aldosterone (ng/dL)
`
`Abiraterone dose (mg)
`250
`500
`750
`1,000
`
`Baseline
`(Day -7)
`
`Day 28
`
`Baseline
`(Day -7)
`
`Day 28
`
`Baseline
`(Day -7)
`
`Day 28
`
`16,000
`
`14,000
`
`12,000
`
`10,000
`
`8,000
`
`6,000
`
`4,000
`
`2,000
`
`0
`
`Corticosterone (ng/dL)
`
`20
`18
`16
`14
`12
`10
`
`2468
`
`0
`
`10
`
`123456789
`
`0
`
`Cortisol (µg/dL)
`
`Testosterone (ng/dL)
`
`Baseline
`(Day -7)
`
`Day 28
`
`Baseline
`(Day -7)
`
`Day 28
`
`Baseline
`(Day -7)
`
`Day 28
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`400
`
`350
`
`300
`
`250
`
`200
`
`150
`
`100
`
`50
`
`0
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`A
`
`Deoxycorticosterone (ng/dL)
`
`B
`
`11-deoxycortisol (ng/dL)
`
`C
`
`DHEA-S (µg/dL)
`
`Fig 1. Changes in mean levels of endocrine steroids from baseline to day 28 of therapy, by dose (A-C), in men with castration-resistant prostate cancer receiving
`abiraterone acetate. DHEA-S, dehydroepiandrosterone sulfate.
`
`1484
`
`© 2010 by American Society of Clinical Oncology
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`4
`
`

`

`Phase I Study of Abiraterone in CRPC
`
`quent cycles, concentrations were lower (approximately 10% to 15%)
`than the highest concentration observed in cycle 1.
`
`Efficacy
`At week 12, confirmed decreases in PSA levels of ⱖ 50% were
`seen in 18 (55%) of 33 patients overall, including nine (47%) of 19
`patients with prior ketoconazole therapy and nine (64%) of 14 pa-
`tients without prior ketoconazole therapy (Fig 3). A maximal PSA
`decrease of ⱖ 50% at any time point was seen in 19 (58%) of 33
`patients, including 10 patients (53%) with prior ketoconazole expo-
`sure and nine patients (64%) without. At 1,000 mg, seven (58%) of 12
`patients had a ⱖ 50% maximal decrease in PSA. Within the prior
`ketoconazole group, confirmed ⱖ 50% decreases in PSA were seen in
`two (50%) of four patients who had discontinued ketoconazole as a
`result of toxicity and in seven (47%) of 15 patients who had discon-
`tinued ketoconazole as a result of disease progression. The median
`time to PSA progression for all patients was 234 days (95% CI, 174 to
`341 days). Among patients with and without prior ketoconazole,
`median time to PSA progression was 283 days (95% CI, 174 days to
`not estimable) and 230 days (95% CI, 90 to 341 days), respectively (Fig
`A4, online only).
`Nine (56%) of 16 patients who previously responded to ketocon-
`azole responded to abiraterone. Seven (37%) of 19 patients who re-
`sponded to ketoconazole did not respond to abiraterone.
`Of three patients who did not respond to ketoconazole, one has
`responded to abiraterone. Of four patients who discontinued keto-
`conazole as a result of toxicity, three responded to abiraterone. Of the
`15 patients who developed ketoconazole-refractory disease (eg, expe-
`rienced progression of disease on ketoconazole after experiencing a
`response), seven (46%) responded to abiraterone.
`
`DISCUSSION
`
`Abiraterone acetate has significant activity in patients with CRPC, as
`evidenced by a PSA response rate of 58% in this phase I trial and
`declines in PSA on all dose levels. Although the utility of using PSA
`reductions as a marker of clinical activity is debated, in general, most
`investigators agree that it is a reasonable tool to screen for activity. The
`activity of abiraterone acetate is attributed to the reduction of the total
`androgen pool, with a reduction in levels of both adrenal androgens
`and testosterone, thereby inhibiting persistent signaling through the
`AR. It is of considerable interest that abiraterone acetate has demon-
`strated activity in patients previously treated with ketoconazole.
`Dose escalation was not discontinued as a result of the presence of
`DLTs. Abiraterone acetate was well tolerated up through the highest
`dose level evaluated (1,000 mg/d) with no MTD observed and no
`apparent toxicity differences among patients who had or had not
`received prior ketoconazole use. On the basis of safety, endocrinologic
`and pharmacokinetic parameters, and indications of activity, an abi-
`raterone acetate dose of 1,000 mg/d is recommended for further study.
`The adverse event and steroid endocrine profiles were consistent
`with anticipated outcomes of selective CYP17 inhibition (decrease in
`androgens and concomitant increase in upstream mineralocorticoid
`production). At the 1,000-mg dose level, hypertension and fatigue
`were the most commonly observed toxicities. The use of beta-
`blockers, diuretics, and eplerenone (often at doses ⬎ 25 mg daily) was
`modestly effective in managing abiraterone-induced hypertension.
`
`(Fig A1, online only). A decrease in cortisol was observed (Fig 1).
`DHEA-S and testosterone levels decreased to undetectable or near
`undetectable levels. At the 1,000-mg dose level, the DHEA-S level
`decreased from baseline values (mean, 49 ␮g/dL; range, 15 to 99
`␮g/dL) to ⱕ 15 ␮g/dL (assay lower limit of quantitation) at day 28 and
`remained at this level at time of progression. For testosterone, corre-
`sponding mean values were 4 ng/dL (range, 1 to 10 ng/dL) at baseline
`and ⱕ 1 ng/dL (range, 1 to 2 ng/dL) at day 28; values remained at ⱕ 1
`ng/dL (range, 1 to 1.5 ng/dL) at time of progression (Fig 2). A possible
`trend in dose-response relationship was observed for deoxycorticoste-
`rone, corticosterone, and 11-deoxycortisol levels, although statistical
`comparison is limited by the small total number. No appreciable
`changes in follicle-stimulating hormone or luteinizing hormone levels
`were seen.
`
`Pharmacokinetics
`Pharmacokinetics were evaluated for all 33 patients. Abiraterone
`acetate was not detected in any sample, suggesting rapid conversion to
`abiraterone. Maximum drug concentrations (Cmax) were achieved
`within 1.5 to 4 hours (time of maximum observed concentration;
`Table 3). Less than proportional increases in both Cmax and AUC0-⬁
`were observed across dose levels in fed and fasted patients (Table 3; Fig
`A2, online only) but were less pronounced among fed patients. The
`small number of patients per cohort and the high degree of interpa-
`tient variability, often approaching 50%, limit further interpretation.
`Nonetheless, abiraterone exposures appeared higher in fed patients
`(Fig A3, online only), possibly suggesting that food may increase
`absorption. Terminal half-life ranged from 5 to 14 hours. At subse-
`
`Abiraterone
`dose (mg)
`250 (n = 2)
`500 (n = 2)
`750 (n = 6)
`1,000 (n = 6)
`
`Baseline (Day -7)
`
`Day 28
`
`Progression
`
`Abiraterone
`dose (mg)
`250 (n = 2)
`500 (n = 2)
`750 (n = 6)
`1,000 (n = 6)
`
`Baseline (Day -7)
`
`Day 28
`
`Progression
`
`1.2
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0
`
`1.2
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0
`
`A
`
`Change From Baseline
`
`B
`
`Change From Baseline
`
`Fig 2. Relative levels of (A) dehydroepiandrosterone sulfate and (B) testoster-
`one (commercial assay) at baseline, at day 28, and at the time of disease
`progression in patients treated with abiraterone acetate, by dose.
`
`www.jco.org
`
`© 2010 by American Society of Clinical Oncology
`
`1485
`
`5
`
`

`

`Ryan et al
`
`Table 3. Pharmacokinetic Parameters of Abiraterone by Noncompartmental Analysis
`
`Abiraterone Acetate Dose
`
`250 mg
`
`500 mg
`
`750 mg
`
`1,000 mg
`
`Fasted
`(n ⫽ 3)
`
`Fed
`(n ⫽ 3)
`
`Fasted
`(n ⫽ 6)
`
`Fed
`(n ⫽ 3)
`
`Fasted
`(n ⫽ 3)
`
`Fed
`(n ⫽ 3)
`
`Fasted
`(n ⫽ 6)
`
`Fed
`(n ⫽ 6)
`
`2.0
`0
`0
`
`283
`142.2
`50.3
`
`1,411
`697.2
`49.4
`
`5.3
`1.7
`31.7
`
`4,288
`1,319.3
`30.8
`
`654
`447.3
`68.4
`
`2.0
`0.1
`3.8
`
`421
`75.8
`18.0
`
`1,387
`290.2
`20.9
`
`5.1
`1.0
`20.3
`
`530
`99.5
`18.8
`
`3,940
`1,275.4
`32.4
`
`1.5
`0.5
`36.5
`
`331
`204.9
`62.0
`
`1,781
`986.8
`55.4
`
`10.6
`6.3
`59.8
`
`5,441
`4,844.5
`89.0
`
`10,252
`12,268.8
`119.7
`
`2.7
`1.2
`43.3
`
`676
`147.9
`21.9
`
`3,840
`1,080.9
`28.2
`
`6.9
`5.7
`82.7
`
`391
`99.1
`25.4
`
`3,418
`1,934.4
`56.6
`
`2.0
`0.1
`2.8
`
`290
`126.6
`43.7
`
`1,665
`704.6
`42.3
`
`7.1
`3.4
`48.6
`
`1,519
`822.7
`54.2
`
`13,688
`4,265.4
`31.2
`
`2.0
`0
`0
`
`1,552
`458.1
`29.5
`
`9,359
`3,338.6
`35.7
`
`7.9
`2.6
`33.2
`
`247
`73.0
`29.6
`
`2,740
`1,084.7
`39.6
`
`1.8
`0.4
`22.3
`
`510
`366.5
`71.9
`
`3,478
`2,012.2
`57.9
`
`14.4
`7.7
`53.3
`
`2,650
`4,617.0
`174.2
`
`25,494
`18,670.2
`73.2
`
`4.0
`0
`0
`
`2,194
`1,096.9
`50.0
`
`14,404
`5,971.0
`41.5
`
`12.5
`1.2
`9.8
`
`231
`97.7
`42.2
`
`4,069
`1,462.6
`36.0
`
`Parameter
`Tmax, hours
`Mean
`SD
`% CV
`Cmax, nM/L
`Mean
`SD
`% CV
`AUC0-⬁, nM/L 䡠 h
`Mean
`SD
`% CV
`t1/2-␭, h
`Mean
`SD
`% CV
`Apparent clearance, L/h
`Mean
`SD
`% CV
`Apparent Vd, L
`Mean
`SD
`% CV
`
`NOTE. Clearance and volume of distribution are calculated as a function of bioavailability. However, the bioavailability of abiraterone is not known.
`Abbreviations: Tmax, time of maximum observed concentration; SD, standard deviation; CV, coefficient of variation; Cmax, maximum concentration; AUC0-⬁, area
`under the curve from the time of dosing extrapolated to infinity; t1/2-␭, terminal half-life; Vd, volume of distribution.
`
`sibly related to a rapid decline in mineralocorticoid levels. This was not
`seen in patients who received hydrocortisone or prednisone. There-
`fore, we suggest that a low dose of a corticosteroid, such as prednisone,
`be administered with abiraterone acetate in future studies to optimize
`the safety profile.
`The endocrine changes observed with abiraterone acetate were
`also consistent with its known inhibitory effects on 17␣-hydroxylase
`and C17,20-lyase activities. Serum DHEA-S and testosterone declined
`substantially at all dose levels. At day 28, increased levels of adrenal
`steroids and upstream precursor molecules, including mineralocorti-
`coids (corticosterone and deoxycorticosterone) were seen, consistent
`with a feedback mechanism resulting from increasing ACTH levels.
`Toxicities of mineralocorticoid excess (hypertension and potassium
`wasting) were mitigated with corticosteroid use as a result of suppres-
`sion of the hypothalamic-pituitary adrenal axis.
`No differences were observed in toxicity or PSA declines between
`fasted and fed patients. Interestingly, a high-fat meal substantially
`increased total drug exposure (AUC) in the fed patients, whereas an
`increased clearance and volume of distribution were observed in the
`fasted state. Although not directly observed, the potential for greater
`drug exposure to increase toxicities cannot be ruled out. To minimize
`diet-related variability in drug exposure, we suggest that future studies
`administer abiraterone acetate in a fasted state.
`Confirmed PSA declines of ⱖ 50% were seen in 58% of patients
`overall, including a 47% PSA response rate in patients with disease
`
`Administration of a corticosteroid was associated with normalization
`of mineralocorticoid levels and improvements in blood pressure. Of
`interest, two patients who received dexamethasone, which has little
`mineralocorticoid activity, experienced orthostatic hypotension, pos-
`
`Abiraterone dose
`250 mg
`500 mg
`750 mg
`1,000 mg
`
`250
`
`200
`
`150
`
`100
`
`50
`
`0
`
`-50
`
`-100
`
`Week 12 PSA Change (%)
`
`Prior ketoconazole (n = 19)
`
`No ketoconazole (n = 14)
`
`Fig 3. Relative change in prostate-specific antigen (PSA) levels at week 12 of
`therapy in men with castration-resistant prostate cancer treated with abiraterone
`acetate. Patients who had received prior ketoconazole therapy appear on the left;
`those who had not received prior ketoconazole appear on the right.
`
`1486
`
`© 2010 by American Society of Clinical Oncology
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`6
`
`

`

`Phase I Study of Abiraterone in CRPC
`
`progression on prior ketoconazole therapy; in phase III trials of keto-
`conazole, the PSA response rate was approximately 30%,11 and phase
`II studies showed a 45% to 65% rate of response.17 Of note, at the time
`of disease progression on ketoconazole,11 adrenal androgen levels
`were increased relative to their nadir, suggesting that the suppressive
`effects of ketoconazole on adrenal androgen synthesis are not durable.
`Furthermore, prolonged disease suppression by ketoconazole may be
`complicated by induction of metabolism or drug-drug interactions.
`By contrast, the suppressive effects of abiraterone on adrenal androgen
`synthesis are durable because progression of disease on abiraterone is
`not accompanied by an increase in adrenal androgens (Fig 2), again
`potentially reflecting the more potent CYP17 inhibitory activity of
`abiraterone compared with ketoconazole. These observations may
`explain why a high proportion of patients were able to benefit from
`abiraterone after ketoconazole. Also of note, the patients with prior
`ketoconazole treatment had experienced longer than average re-
`sponses to ketoconazole (15 months v reported median responses of
`approximately 5 months) and thus may represent a group of patients
`more likely to harbor disease that is dependent on CYP17-mediated
`androgen production. Although this may be reflective of an unin-
`tended selection bias, the high rate of response to abiraterone in
`ketoconazole-exposed patients is further evidence of the superior po-
`tency of abiraterone compared with ketoconazole. More analysis of
`this relationship in future studies is warranted.
`From our data, it cannot be determined whether pretreatment
`adrenal androgen levels can identify patients more likely to respond to
`abiraterone, as has been suggested with ketoconazole,18,19 or whether
`changes in adrenal androgen levels correlate with clinical outcomes.
`However, such correlations are of interest and should be pursued. The
`exclusion of patients with prior chemotherapy for CRPC in this study
`was intended to allow for preliminary evaluation of abiraterone ace-
`tate in a patient population typically treated with secondary hormonal
`manipulation, chiefly as a means of delaying use of traditional cyto-
`toxics. Ongoing studies are evaluating abiraterone in patients with
`both chemotherapy-refractory and chemotherapy-naïve CRPC.
`Despite these findings, several unaddressed issues remain. First,
`although abiraterone did not cause adrenal insufficiency in any pa-
`tients, the impact of concurrent prednisone on response proportion
`and durability or long-term toxicity is not known. Second, despite the
`high PSA decline rate, the relationship between PSA decline and sur-
`vival in the prechemotherapy setting is undefined. Finally, the obser-
`vation of abiraterone efficacy in a ketoconazole-refractory CRPC
`population requires prospective validation. Such studies are ongoing.
`In summary, these data suggest that abiraterone is an active
`agent
`for CRPC and is associated with acceptable toxicity.
`
`Mineralocorticoid-induced hypertension is a unique toxicity but is
`controlled by corticosteroids. Preliminary observations of responses
`to abiraterone in patients with prior ketoconazole therapy suggest that
`cross-resistance between these therapies may not exist. Further defin-
`itive studies of this agent are warranted.
`
`AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
`OF INTEREST
`
`Although all authors completed the disclosure declaration, the following
`author(s) indicated a financial or other interest that is relevant to the subject
`matter under consideration in this article. Certain relationships marked
`with a “U” are those for which no compensation was received; those
`relationships marked with a “C” were compensated. For a detailed
`description of the disclosure categories, or for more information about
`ASCO’s conflict of interest policy, please refer to the Author Disclosure
`Declaration and the Disclosures of Potential Conflicts of Interest section in
`Information for Contributors.
`Employment or Leadership Position: Thian Kheoh, Cougar
`Biotechnology (C); Arturo Molina, Cougar Biotechnology (C)
`Consultant or Advisory Role: Charles J. Ryan, Cougar Biotechnology
`(U); Matthew R. Smith, Cougar Biotechnology (U); Philip Kantoff,
`Cougar Biotechnology (C); Eric J. Small, Cougar Biotechnology (C)
`Stock Ownership: Thian Kheoh, Cougar Biotechnology; Arturo Molina,
`Cougar Biotechnology Honoraria: None Research Funding: Philip
`Kantoff, Cougar Biotechnology; Florence Raynaud, Cougar
`Biotechnology; Vanessa Martins, Cougar Biotechnology Expert
`Testimony: None Other Remuneration: None
`
`AUTHOR CONTRIBUTIONS
`
`Conception and design: Charles J. Ryan, Vanessa Martins,
`Arturo Molina
`Administrative support: Jennifer Kim
`Provision of study materials or patients: Charles J. Ryan, Lawrence
`Fong, Philip Kantoff, Gloria Lee, Arturo Molina
`Collection and assembly of data: Charles J. Ryan, Matthew R. Smith,
`Jonathan E. Rosenberg, Philip Kantoff, Florence Raynaud, Vanessa
`Martins, Thian Kheoh, Jennifer Kim, Arturo Molina, Eric J. Small
`Data analysis and interpretation: Charles J. Ryan, Matthew R. Smith,
`Lawrence Fong, Jonathan E. Rosenberg, Philip Kantoff, Florence
`Raynaud, Vanessa Martins, Gloria Lee, Thian Kheoh, Jennifer Kim,
`Arturo Molina, Eric J. Small
`Manuscript writing: Charles J. Ryan, Matthew R. Smith, Lawrence Fong,
`Jonathan E. Rosenberg, Philip Kantoff, Arturo Molina, Eric J. Small
`Final approval of manuscript: Charles J. Ryan, Matthew R. Smith,
`Lawrence Fong, Jonathan E. Rosenberg, Philip Kantoff, Florence
`Raynaud, Vanessa Martins, Gloria Lee, Thian Kheoh, Jennifer Kim,
`Arturo Molina,