VOLUME 28
`
`· NUMBER 9
`
`· MARCH 20 2010
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`Phase II Multicenter Study of Abiraterone Acetate Plus
`Prednisone Therapy in Patients With Docetaxel-Treated
`Castration-Resistant Prostate Cancer
`Daniel C Danila, Michael]. Morris, JohannS. de Bono, Charles f. Ryan, Samuel R. Den meade,
`Matthew R. Smith, Mmy-Ellen Taplin, Glenn f. Bubley, Thian Kheoh, Christopher Haqq, Arturo Molina,
`Aseem
`Michael Koswiszka, Steve M. Larson, Lawrence H.
`Martin Fleisher,
`and Howard I. Selzer
`
`See accompanying editorial on page 1447 and articles on pages 1481 and 1489
`
`A B S T R A C T
`
`Purpose
`Persistence of ligand-mediated androgen receptor signaling has been documented in castration(cid:173)
`resistant prostate cancers (CRPCs). Abiraterone acetate (AA) is a potent and selective inhibitor of
`CYP17, which is required for androgen biosynthesis in the testes, adrenal glands, and prostate
`tissue. This trial evaluated the efficacy and safety of AA in combination with prednisone to reduce
`the symptoms of secondary hyperaldosteronism that can occur with AA monotherapy.
`
`Patients and Methods
`treatment failure with
`Fifty-eight men with progressive metastatic CRPC who
`docetaxel-based chemotherapy received AA (1 ,000 mg daily) with prednisone (5 mg twice
`daily). Twenty-seven (47%) patients had received prior ketoconazole. The primary outcome
`was 2: 50% prostate-specific antigen (PSA) decline, with objective response by Response
`criteria, and changes in Eastern Cooperative Oncology
`Evaluation Criteria in Solid Tumors
`Group
`performance status (PS) and circulating tumor cell (CTC) numbers. Safety was
`also evaluated.
`
`Results
`A 2: 50% decline in PSA was confirmed. in 22 (36%) patients, including 14 (45%) of 31
`ketoconazo!e-naTve and seven (26%) of 27 ketoconazole-pretreated patients. Partial responses
`were seen in four (18%) of 22 patients with RECIST-evaluable target lesions. Improved ECOG PS
`was seen in 28% of patients. Median time to PSA progression was 169 days (95% Cl, 82 to 200
`days). CTC conversions with treatment from 2: 5 to< 5 were noted in 10 (34%) of 29 patients.
`The majority of AA-related adverse events were grade 1 to 2, and no AA-related grade 4 events
`were seen.
`
`Conclusion
`AA plus prednisone was well tolerated, with encouraging antitumor activity in heavily pretreated
`CRPC patients. The incidence of mineralocorticoid-related toxicities (hypertension or hypokalemia)
`was reduced by adding low-dose prednisone. The combination of AA plus prednisone is
`recommended for phase ill investigations.
`
`J Clin Oneal 28:1496-1507. © 2010 by American Society of Clinical Oncology
`
`Prostate cancer progression despite castrate levels
`of testosterone is associated with a rising prostate(cid:173)
`specific antigen (PSA) level and represents a tran(cid:173)
`sition to the lethal phenotype of the disease to
`which most patients eventually succumb. The rise
`in PSA, an indication that androgen receptor
`(AR) signaling has been reactivated, is the result of
`se,lective and/or adaptive changes in the AR itself
`
`that are oncogenic for growth, of which AR over(cid:173)
`expression is the most common. 1 Tumor levels of
`ligand have received less attention. In 1984, Geller
`et af documented elevated levels of androgens in
`tissue homogenates of the prostates of men who
`were progressing on medical or surgical castra(cid:173)
`tion. Adrenal androgen synthesis was the postu(cid:173)
`lated source, although a failure to completely
`suppress intratumoral androgens could not be
`excluded. The finding of mcreased intratumoral
`
`From the Department of Medicine, Joan
`and Sanford E. Weill College of Medicine
`of Cornell University, Ithaca: Clinical
`Laboratories, Department of Radiology,
`and Sidney Kimmel Center ior Prostate
`and Urologic Cancers, Memorial Sloan(cid:173)
`Kettering Cancer Center, New York, NY;
`Cancer Research United Kingdom Centre
`for Cancer Therapeutics, Institute of
`Cancer Research, Royal Marsden Hospi(cid:173)
`tal. London, United Kingdom; University
`oi California-San Francisco Comprehen(cid:173)
`sive Cancer Center, San Francisco;
`Department of Clinical Resear;:;h and
`Development. Cougar Biotechnology, Los
`Angeles, CA; Chemical Therapeutics
`Program, The Sidney Kimmel Compre(cid:173)
`hensive Cancer Center, The Johns
`Hopkins University School of Medicine,
`Baltimore, MD; Division of Hematology(cid:173)
`Oncology, Massachusetts General Hospi(cid:173)
`tal; Dana-Farber Cancer Institute, Harvard
`Medical School, and Beth Israel Deacon(cid:173)
`ess Medical Center, Boston, MA.
`
`Submitted August 31, 2009; accepted
`November 16, 2009; published online
`ahead of print at www.jco.org on
`February 16, 2010.
`
`Supported by Cougar Biotechnology,
`the Memorial Sloan-Kettering Cancer
`Center Specialized Program of
`Research Excellence (SPORE) Grant in
`Prostate Cancer (P50 CA92629), the
`Department of Defense Prostate
`Cancer Research Program IPC051382l
`and the Prostate Cancer Foundation.
`
`Presented in part at the 45th Annual
`Meeting of the American Society of Clini(cid:173)
`cal Oncology lASCO), May 29-June 2,
`2009, Orlando, FL. and the 44th Annual
`Meeting of ASCO, May 30.June 3, 2008,
`Chicago, IL
`
`Authors' disclosures of potential con(cid:173)
`flicts of interest and author contribu(cid:173)
`tions are found at the end of this
`article.
`
`Corresponding author: Howard L Scher,
`MD, Genitourinary Oncology Service,
`Department of Medicine, Sidney Kimmel
`Center for Prostate and Urologic Cancers,
`Memorial Sloan-Kettering Cancer Center.
`1275 York Ave, New York, NY 1 0065;
`e-mail: Scherh@mskcc.org.
`
`© 2010 by American Society of Clinical
`Oncology
`
`0732-1 B3X/1 0/2809-1496/$20.00
`
`DOl: 1 0.1200/JC0.2009.25.9259
`
`1496 © 2010 by American Society of Clinical Oncology
`
`WCK1024
`Page 1
`
`

`
`Phase II Study of Abiraterone Acetate in CRPC
`
`androgens was subsequently confirmed in microdissected lo(cid:173)
`cally recurrent and castration-resistant primary and metastatic
`lesions.3-6 In 2004, Holzbeierlein et al' first
`a microarray
`analysis of newly diagnosed primary and metastatic and separately
`posthormone-treated primary and progressive castration-resistant
`prostate cancers (CRPCs) that showed an up to five-fold induction
`of several enzymes involved in steroid hormone production. The
`9 suggested the pos(cid:173)
`finding, subsequently confirmed by others,8
`'
`sibility of intracrine
`as an additional mechanism of
`AR reactivation.
`Abiraterone (CB7630, Cougar Biotechnology, Los Angeles, CA)
`is a novel, selective, irreversible, and potent inhibitor of 17-[alpha](cid:173)
`hydroxylase/17,20-lyase (CYP17) enzymatic activity that has re(cid:173)
`cently been demonstrated to further reduce testosterone levels in the
`blood to undetectable range ( < 1 ng/dL), 10
`11 and is
`to
`'
`reduce de novo intratumor androgen synthesis.12 Significant antitu(cid:173)
`mor effects were seen in patients with progressive CRPC who had not
`received prior chemotherapy, where
`hormonal therapies
`are traditionally used.ll,l3 Ketoconazole, a weak inhibitor of adrenal
`steroid synthesis that suppresses many cytochrome P450 enzymes and
`other enzymes involved in the conversion of cholesterol to preg(cid:173)
`nenolone, has also shown activity in the same clinical context14
`15 but
`•
`18
`is associated with significant tox:icities. 16
`-
`Recognizing that PSA levels also rise in patients who are
`progressing after treatment with cytotoxic agents, we postulated
`that these tumors might also be sensitive to a potent AR signaling
`inhibitor. In a separate trial, we showed significant antitumor
`effects of abiraterone acetate (AA) monotherapy in this patient
`group, emphasizing further how considering these tumors as
`hormone-refractory can deny patients effective therapies. 19 The
`adverse events seen with AA monotherapy were
`those asso-
`ciated with secondary hyperaldosteronism,
`hypokale-
`mia, fluid retention, and hypertension that required treatment
`with the selective aldosterone inhibitor eplerenone or low-dose
`steroids to suppress the hypothalamic-pituitary-adrenal
`blunting the feedback rise in adrenocorticotropic hormone to re(cid:173)
`duce production of adrenal steroids with mineralocorticoid activ-
`11'20 Anticipating phase III development, we designed this study
`to confirm the antitumor activity of AA in patients with CRPC after
`failure of docetaxel-based chemotherapy using the proposed reg(cid:173)
`istration
`of AA at 1,000 mg daily in combination with
`prednisone at 5 mg twice daily, and separately, to begin to address
`the influence on outcome of the number and type of prior hor(cid:173)
`mone treatments, particularly ketoconazole.21 Importantly, the
`evaluation of this steroid combination was further supported by
`our work indicating that low-dose steroids can reverse clinical AA
`resistance and decrease steroid precursors upstream ofCYP17 that
`can activate AR signaling. Recognizing that PSA changes may not
`be a reliable indicator of the antitumor effects of an AR signaling(cid:173)
`directed therapy and that more informative indicators of clinical
`benefit represent a critical unmet need for the management of
`we also evaluated pre- and post~therapy circulating tumor
`cell ( CTC) number using an analytically valid assay that is cleared
`by the US Food and Drug Administration for use as an aid to
`monitoring treatment and prognosis in patients with breast,22
`colorectal,23 and prostate cancer.24
`
`Patients
`Castrate men (serum testosterone <50 ngfdL [< 2.0 nmol/L]) with
`metastatic prostate cancer who had experienced treatment failure >vith andro(cid:173)
`gen deprivation therapy and docetaxel-based chemotherapy were eligible.
`Disease progression was defined as documented PSA progression according to
`Prostate Specific Antigen Working Group 1 criteria25 and a PSA >
`or
`nn11Prf1VP progression by Response Evaluation Criteria in Solid Tumors
`(RECIST) criteria26 for patient~ \vith measurable disease. Patients had to
`have received prior chemotherapy 'vith docetaxel, and treatment ;v:ith up
`to two prior chemotherapy regimens was permitted. Prior treatment with
`ketoconazole was allowed and was recorded separately. Eligibility criteria
`also included Eastern Cooperative Oncology Group (ECOG) performance
`status (PS) of :5: 2, (Kamofsky PS :2: 50%), normal serum potassium, and
`adequate hematologic, hepatic, and renal function. With the exception of
`luteinizing hormone-releasing hormone agonists, a minimum of 4 weeks
`must have elapsed from discontinuation of prior prostate cancer therapies and
`a minimum of 6 weeks for antiandrogen therapy, Patients were excluded if
`they had brain metastases or spinal cord compression, active autoimmune
`disease requiring corticosteroid therapy, uncontrolled hypertension, a de(cid:173)
`pressed cardiac ejection fraction or history of cardiac failure (New York Heart
`Association class III or IV), or a serious concurrent medical illness. The trial
`protocol was approved by the institutional review board at each site and
`was conducted in accordance with the Declaration
`current US
`
`Characteristic
`
`Age. years
`Median
`Range
`ECOG performance status
`0
`
`.2
`Unknown
`Gleason score
`Median
`Range
`Baseline PSA, ng/mL
`Median
`Range
`Involved metastatic sites
`Visceral (with or without bone or soft tissue)
`Bone only
`Soft tissue only
`Bone and soft tissue only
`Prior hormonal therapies
`LHRH agonists
`Orchiectomy
`Antiandrogens
`Diethylstilbestrol
`Steroids
`Dexamethasone
`Other
`Ketoconazole
`Prior lines of chemotherapy
`1
`> 1
`
`No. of
`Patients
`
`69.5
`44-86
`
`24
`31
`2
`
`7
`5-10
`
`189.6
`10.1-3,846
`
`13
`11
`8
`26
`
`57
`3
`53
`8
`21
`5
`20
`27
`
`44
`14
`
`%
`
`41
`53
`3
`2
`
`22
`19
`14
`45
`
`98
`5
`91
`14
`36
`9
`34
`47
`
`76
`24
`
`Abbreviations: ECOG, Eastern Cooperative Oncology Group; PSA, prostate(cid:173)
`specific antigen; LHRH, luteinizing hormone--releasing hormone.
`
`lVlvw.jco,org
`
`© 2010 by American Society of Clinical Oncology
`
`1497
`
`WCK1024
`Page 2
`
`

`
`Danila et al
`
`Food and Drug Administration Good Clinical Practices, and local ethical
`and legal requirements.
`Study Design
`After written informed consent was obtained, eligible patients in this
`multicenter phase II clinical trial receivedM at 1,000 mg (four 250-mgtablets
`daily in the morning after an overnight fast) concurrently with prednisone at 5
`mg twice daily. Treatment was administered in 28-day cycles, and up to 12
`cycles of therapy were permitted; continuation beyond 12 cycles was allowed
`on approval by the investigators and sponsor.
`Patient Evaluation
`while
`Patients were seen and examined at the beginning of every
`receiving treatment, and adverse events were recorded using the National
`Cancer Institute Common Toxicity Criteria, version 3.0. Potential attributions
`toM and prednisone were recorded separately. A CBC, chemistry panel, PSA,
`and
`levels were evaluated monthly.
`Antitumor Outcomes
`The primary study objective was determination of the proportion of
`patients achieving adecline in PSA ~ 50% according to Prostate Specific
`Antigen Working Group 1 criteria (PSAresponse). The maximal and 12-week
`post-therapy declines in PSA were recorded using waterfall plots. The maximal
`decline had to be confirmed by a second value obtained~ 4 weeks later.25
`Patients who had metastatic disease evident on baseline
`(computed
`tomography scan, magnetic resonance imaging, or bone scan) had follow-up
`studies at 3-month intervals. Measurable disease response rate was reported
`using the RECIST criteria, while post -treatment changes on radionuclide bone
`scan were reported as stable or progression
`assessment.
`Time to PSA progression was calculated for
`with PSA decline
`~ 50% from baseline at the time the PSA increased to 50% above the nadir and
`was > 5 ng/rnL. For those not meeting the PSA decline criteria, time to PSA
`progression was the time when PSA increased by 25% from baseline.
`Other end points recorded were changes in ECOG PS, and
`post-therapy CTC counts (number ofcells/7.5 rnL ofblood) wer.e enumer-
`
`ated separately using the CellTracks system (Veridex, Raritan, NJ), as
`28
`described previously.27•
`
`Statistical Analysis
`The primary end point of the trial was the proportion of patients who
`achieved a PSA decline of~ 50% from baseline that was confirmed by a second
`value following treatment 1Nith AA plus prednisone. The combination would
`be considered worthy of further study if~ 30% of patients met the end point
`and not worthy of further study if fewer than 15% achieved the end point.
`With a population of 50 patients, the null hypothesis would be rejected and
`further study of the combination would be warranted if> 25% of eligible and
`treated patients had a~ SOo/o decline in PSA (alpha of 6% with 86% power).
`
`Patients
`Between June 2007 and November 2007, 58 men with CRPC
`were enrolled across seven study centers: six in the United States and
`one in the United Kingdom. Patient demographics and baseline char(cid:173)
`acteristics are listed in Table 1. All were heavily pretreated with a
`number ofhormonal therapies that included a median of four (range,
`one to eight) prior antiandrogens in 52 (91 %) and estrogens in nine
`(16%), while 27 (47%) had prior ketoconazole. While all had been
`treated with prior docetaxel, 24% had also received a second chemo(cid:173)
`therapy regimen. Consistent with the advanced state of the popula(cid:173)
`tion, only 11 (19%) had disease limited to bone, while 13 (22%) had
`visceral spread, and 34 patients (59%) had soft tissue disease with or
`without osseous spread. The median PSA
`at baseline was 190
`ng!ml (range, 10 to 3,846 ng!ml). The median testosterone level was
`4.8 ng!dL (range, below limit of detection [0.05] to 30.5 ng!dL).
`
`A
`;:;'2.
`
`<(
`UJ
`CL
`
`100
`
`50
`
`0
`
`-50
`
`-100
`
`B
`;:;'2.
`
`100
`
`50
`
`0
`
`-50
`
`<(
`UJ
`CL
`N
`
`~
`~ -100
`$
`
`50% PSA decline, 8/27 (29.6%)
`
`50% PSA decline, 7/31 (54.8%)
`
`Fig 1. Changes in prostate-specific anti(cid:173)
`gen (PSA) levels with abiraterone acetate
`plus prednisone. Waterfall plots of (A)
`maximum PSA change and (BJ change at
`week 12. Patients with prior ketoconazole
`exposure appear on the left side of the
`panel in blue and those without prior ke(cid:173)
`toconazole exposure appear on the right
`side of the panel in gold.
`
`50% PSA decline, 7/27 (25.9%}
`
`50% PSA decline, 14/31 (45.1%)
`
`!lij\@i%$ Prior ketoconazole exposure (n = 27)
`
`Reference lines:
`
`-
`
`-90%
`
`No prior ketoconazole exposure (n = 31)
`
`@ PSA value clipped
`
`---50%
`
`---30%
`
`1498 © 2010 by American Society of Clinical Oncology
`
`JOURNAL OF CL!NlCAL ONCOLOGY
`
`WCK1024
`Page 3
`
`

`
`Phase II Study of Abiraterone Acetate in CRPC
`
`·
`
`Table 2. ECOG Performance Score
`
`=58)
`
`Postbaseline ECOG Performance Score
`
`0
`
`2
`
`No. of
`No. of
`No. of
`No. of
`Patients Patients % Patients % Patients %
`
`24
`31
`2
`
`22
`14
`1
`37
`
`64
`
`2
`15
`1
`18
`
`2
`
`2
`
`3
`
`31
`
`Baseline ECOG
`Performance
`Score
`
`0
`
`2
`Total·
`
`Abbreviation: ECOG, Eastern Cooperative Oncology Group.
`•one patient did not have baseline ECOG recorded.
`
`Antitumor Effects
`PSk A waterfall plot of the maximal PSA decline and 12-week
`post-therapy PSA changes is shown in Figure 1. Overall, the propor(cid:173)
`tion ofpatients achieving a 50% or greater maximal decline in PSA was
`of 58; 95% CI, 30% to
`including 30% (8
`95%
`43%
`13% to 47%) of those who had received previous ketoconazole and
`of3 i; 95% CI, 3 7% to 73%) of those who were ketoconazole(cid:173)
`55%
`nai:ve. At the 12-week assessment, the overall proportion of patients
`achieving a 2: 50% decline in PSA was 36% (21 of 58; 95% CI, 24% to
`95% CI, 9% to 435%) of those who had
`48%), including26% (7
`received previous ketoconazole and 45% (14
`95% CI, 27% to
`63%) of those who were ketoconazole-naive. The differences in the
`proportion showing declines in PSA were not statistically significant.
`Overall, confirmed PSA responses of 2: 30%, 2: 50%, and 2: 90%
`decline were observed in 47o/o, 36%, and 16% of patients, respectively.
`In the prior ketoconazole versus ketoconazole-nai:ve patients, the con(cid:173)
`firmed PSA decline of;::: 30%, :2':: 50%, and 2 90o/o were, respectively,
`nine (33%) versus 18 (58%), seven (26%) versus 14 (45%), and zero
`(Oo/o) versus nine (29o/o) patients.
`
`Soft tissue. Twenty-two of 28 patients with baseline scans had
`lesions assessed by computed tomography in1aging; of these 22
`patients, partial responses were seen in four (18%), stable disease
`lasting more than 3 months in 13 (59%), and disease progression in
`five (23o/o).
`Osseous disease. Bone scans provided objective radiologic re(cid:173)
`sponse information for 27 evaluable patients of the 34 patients with
`baseline scans. By investigator assessment, 16 (59%) patients had
`stable disease and 11 ( 41 o/o) patients experienced disease progression.
`Clinical benefit and PS. Changes in ECOG PS from baseline were
`Overall, 16
`evaluated as an indication of clinical benefit
`patients (28o/o) had an improvement in ECOG PS, with 14 patients
`improving from PS 1 to PS 0, and one patient each improving from PS
`2 toPS l or PS 0. Four patients (7%) had a worsening PS, with tv.;ro
`patients each changing from baseline PS 0 to PS 1 or PS 1 to PS 2. PS
`remained stable among the remaining 3 7 { 64%) patients.
`Time to progression The overall median time to PSA progres(cid:173)
`sion was 169 days (95% CI, 86 to 200 days); based on prior exposure to
`ketoconazole, the median time to PSA progression was 198 days (95%
`82 to 393 days) among ketoconazole-nai:ve patients and 99 days
`(95% CI, 57 to 169 days) amongketoconazole-treated patient~ (Fig2).
`CTCs. Cell counts were available for all38 patients treated at the
`Memorial Sloan-Kettering Cancer Center and four patients treated at
`the Royal Marsden
`Overall, 29 ( 69%)
`had unfavor(cid:173)
`able baseline counts (:2:: 5 cells/7.5 mL blood), of which 10 (34%)
`converted to a favorable count after treatment (Table 3).
`
`Safety and Tolerability
`The combination of AA and prednisone was well tolerated in this
`heavily pretreated population. Grade 3 or 4 adverse events occurred
`No significant hypertension or hypokalemia
`infrequently (Table
`were noted as clinical signs of mineralocorticoid.excess with the pro(cid:173)
`sne'cti1Te addition of prednisone. No patients required treatment with
`mineralocorticoid antagonist eplerenone on this trial. Spinal cord
`
`1.00
`
`0.75
`
`0.50
`
`0.25
`
`- - Keto: median, 99 days (95% Cl, 57 to 169 days)
`~ No Keto: median, 198 days (95% Cl, 82 to 393 days)
`I
`Censored
`
`Fig 2. Time to prostate-specific antigen
`(PSA) progression with abiraterone acetate
`and prednisone in patients with and without
`prior ketoconazole (Keto) exposure.
`
`0
`
`40
`
`80
`
`120
`
`160
`
`200
`
`240
`280
`320
`Study Day
`
`360
`
`400
`
`440
`
`480
`
`520
`
`560
`
`www.jco.o.g
`
`© 2010 by American Society of Clinical Oncology
`
`1499
`
`WCK1024
`Page 4
`
`

`
`Danila et al
`
`Table 3. Patients With High CTC Counts at Baseline Stayed on Treatment
`for a Shorter
`Unless Counts
`With Treatment
`
`CTC/7.5 ml of Blood
`Baseline < 5 CTC (n
`13)
`Post-treatment CTC 2 5 (n
`Post-treatment CTC < 5 (n
`Baseline 2 5 CTC (n = 29)
`Post-treatment CTC 2 5 (n = 19)
`Post-treatment CTC < 5 (n = 10)
`
`4)
`9)
`
`Abbreviation: CTC, circulating tumor cell.
`
`Time on Protocol (weeks)
`
`,;:; 12
`
`12-24
`
`> 24
`
`9
`
`4
`
`7
`3
`
`2
`4
`
`3
`6
`
`compressions were seen in two (3%) patients, which were deemed
`related to disease progression.
`
`This study is the second trial showing the activity of AA in patients
`with castration-resistant prostate cancer who have progressed on
`chemotherapy, and the first to explore the
`regimen
`currently under evaluation in two prospective
`phase
`III, placebo-controlled registration trials with primary end points
`of survival and progression-free survival (WW>v.dinicaltrials.gov,
`30 Antitumor activity was
`NCT00638690, and NCT00887l98)?9
`'
`demonstrated on the basis of post-therapy PSA declines, changes in
`soft tissue disease by RECIST, the lack of progression :in bone, and
`unfavorable to favorable changes in CTCs assessed ·with an analyt(cid:173)
`ically valid assay cleared by the US Food and Drug Admiristration
`for monitoring treatment effects in CRPC. The results show that the
`decision to treat a patient with progressive castration-resistant disease
`with chemotherapy does not necessarily mean that the tumor is resis(cid:173)
`tant to further hormone treatments.
`Noteworthy in this trial was the lower incidence ofhypokalernia,
`hypertension, and fluid retention (5%, < 5%, and < 10%, respec(cid:173)
`tively) compared with 55%, 17%, and 15%, respectively, relative to
`our separate study of AA ·without prednisone. 19 The hyperaldoste(cid:173)
`ronism syndrome developed in the absence of concomitant use of
`low-dose steroids frequently required treatment w:ith either a miner-
`
`Table 4. Incidence of Most Frequent (;,: 5%) Treatment-Related Adverse
`Events (N = 58)
`
`Grade 1
`
`Grade 2
`
`Grade 3
`
`Adverse Event
`
`No.
`
`Nausea
`Vomiting
`Diarrhea
`Constipation
`Fatigue
`Edema peripheral
`AST
`ALT
`Hypokalemia
`Dyspnea
`
`8
`5
`5
`3
`9
`4
`3
`2
`3
`2
`
`%
`
`14
`9
`9
`5
`16
`7
`5
`3
`5
`3
`
`No.
`
`%
`
`No.
`
`o/o
`
`0
`2
`0
`0
`9
`1
`3
`1
`0
`4
`
`0
`0
`0
`0
`1
`0
`0
`0
`0
`0
`
`3
`
`16
`2
`5
`2
`
`7
`
`2
`
`Grade 4
`No.
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`NOTE: Two patients experienced hypertension, one each of grade 1 and
`grade 2.
`
`alocorticoid antagonist (eplerenone) or low-dose glucocorticoids.
`These data, coupled with the high frequency of comorbid conditions
`in this group and the risk of adrenal insufficiency in patients receiving
`glucocorticoids with prior docetaxel treatments, provided strong sup(cid:173)
`port for the combination of AA plus prednisone as the preferred
`regimen for further development
`This trial is, to the best of our knowledge, the first to address the
`effect of prior ketoconazole exposure on outcome, although .the time
`interval between prior ketoconazole therapy and protocol entry was
`highly variable, given that all of the patients were treated with chem(cid:173)
`otherapy in this interval. Patients with prior exposure to treatment
`and possible therapy-related selection pressure with ketoconazole h.ad
`an inferior percentage of PSA decline by 2: 50% compared WJth
`patients without prior ketoconazole exposure. The time to PSA pro(cid:173)
`gression tended to be shorter in patients with prior ketoconazole
`exposure compared with ketoconazole-naive patients. Although th:is
`difference did not reach statistical significance, these findings were
`considered in the design of the exclusion criteria for this phase III trial
`of AA and prednisone in patients with castrate metastatic prostate
`cancer postdocetaxel treatment failure. Unfortunately, the response to
`prior treatment with ketoconazole was not known, so the question of
`cross-resistance could not be fully addressed. These important find-
`will be addressed in the future in a dedicated trial. 13
`Given the modest association with changes in PSA and the limi(cid:173)
`tations of imaging distant metastases, there is an unmet medical need
`to develop tumor-specific markers to aid the selection of tar:;;etE~d
`therapies and to assess clinical outcome, Using a US Food and Drug
`Administration-cleared, analytically valid assay for CTC enumeration
`run in a Clinical Laboratory Improvement Amendments-certified
`laboratory, we have shown that CTC counts are prognostic pretherapy
`33
`and the change in CI'Cnumberpost-therapyispredictive ofsurvival31
`-
`The CTC conversion rate after treatment with AA was also asso(cid:173)
`ciated with an extended time on treatment. The number. of patients
`treated in f4is study was too small to further explore associations •vith
`clinical outcome.
`In conclusion, this study showed biochemical, CTC, and radio(cid:173)
`logic evidence to support the evaluation of tllis AA and prednisone
`schedule in patients with progressive CRPC in a randomized study in
`the postchemotherapy
`with the primary end point of overall
`survival. Importantly, the trial also includes an evaluation of ere num(cid:173)
`ber as an
`response biomarker in the phase III trial of AA plus
`prednisone versus placebo. Moreover, these data indicate that the discov(cid:173)
`ery and development of drugs targeting steroid receptor signaling
`remain critically important for improving outcomes of this disease.
`
`Although all authors completed the disclosure declaration, the following
`autlwr(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 informatiou about
`AS CO's ca~zflict of interest policy, please refer to the Author Disclosure
`Declaration and the Disclosures of Potential Conflicts of Interest section in
`.
`Informatioll for Contributors.
`Employment or Leadership Position: Thian Kheoh, Cougar Biotechnology
`(C); Christopher Haqq, Cougar Biotechnology (C); Arturo Molina, Ortho
`
`15011 © 2010 by American Society of Clinical Oncology
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`WCK1024
`Page 5
`
`

`
`Phase II Study of Abiraterone Acetate in CRPC
`
`Biotech/Cougar Biotechnology (C) Consultant or Advisory Role: Daniel
`C. Danila, Cougar Biotechnology (U); JohannS. de Bono, Cougar
`Biotechnology (U); Matthew R. Smith, Cougar Biotechnology (U); Steve M.
`Larson, Cougar Biotechnology (C); Howard I. Scher, Cougar Biotechnology
`(C), Veridex (U) Stock Ownership: Thian Kheoh, Cougar Biotechnology
`Honoraria: None Research Fnnding: Mary-Ellen Taplin, Cougar
`Biotechnology; Howard I. Scher, Cougar Biotechnology, Vecidex Expert
`Testimony: None Other Remuneration: None
`
`Conception and design: Daniel C. Danila, JohannS. de Bono,
`Christopher Haqq, Howard I. Scher
`Financial support: Christopher Haqq, Arturo Molina
`Administrative support: Christopher Haqq, Arturo Molina,
`Howard I. Scher
`
`Provision of study materials or patients: Daniel C. Danila, Michael J.
`Morris, I ohann S. de Bono, Charles J, Ryan, Matthew R. Smith,
`Mary-Ellen Taplin, Glenn J. Bubley, Christopher
`Howard I. Scher
`Collection and assembly of data: Daniel C. Danila, JohannS. de Bono,
`Charles J. Ryan,
`Thian Kheoh,
`Haqq,
`Arturo Molina, Aseem Anand, Michael Koscuiszka, Howard I. Scher
`Data analysis and interpretation: Daniel C. Danila, Michael J. Morris,
`Samuel R. Denmeade, Mary-Ellen Taplin, Glenn J. Bubley, Thian Kheoh,
`Christopher Haqq, Arturo Molina, Aseem Anand, Michael Koscuiszka, Steve
`M. Larson, Lawrence H. Schwartz, Martin Fleisher, Howard I. Scher
`Manuscript writing: Daniel C. Danila, JohannS. de Bono, Samuel R.
`Denmeade, Mary-Ellen Taplin, Glenn J. Bubley, Thian Kheoh,
`Christopher Haqq, Arturo Molina, Howard I. Scher
`Final approval of manuscript: Daniel C. Danila, Michael J. Morris,
`JohannS. de Bono, Charles J. Ryan, Samuel R. Denmeade, Matthew R.
`Smitb, Mary-Ellen Taplin, Glenn J. Bubley, Thian Kheoh, Christopher
`Haqq, Arturo Molina, Aseem Anand, Michael Koscuiszka, Steve M.
`Larson, Lawrence H. Schwartz, Martin Fleisher, Howard I. Scher
`
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