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
`
`Significant and Sustained Antitumor Activity in Post-
`Docetaxel, Castration-Resistant Prostate Cancer With the
`CYP17 Inhibitor Abiraterone Acetate
`Alison H.M. Reid, Gerhardt Attard, Daniel C. Danila, Nikhil Babu Oommen, David Olmos, Peter C. Fong,
`L. Rhoda Molife, Joanne Hunt, Christina Messiou, Christopher Parker, David Dearnaley, Joost F. Swennenhuis,
`Leon W.M.M. Terstappen, Gloria Lee, Thian Kheoh, Arturo Molina, Charles J. Ryan, Eric Small,
`Howard I. Scher, and Johann S. de Bono
`See accompanying editorial on page 1447 and articles on pages 1481 and 1496
`
`A
`
`B
`
`S
`
`T
`
`R
`
`A
`
`C
`
`T
`
`Purpose
`The principal objective of this trial was to evaluate the antitumor activity of abiraterone acetate, an
`oral, specific, irreversible inhibitor of CYP17 in docetaxel-treated patients with castration-resistant
`prostate cancer (CRPC).
`Patients and Methods
`In this multicenter, two-stage, phase II study, abiraterone acetate 1,000 mg was administered
`once daily continuously. The primary end point was achievement of a prostate-specific antigen
`(PSA) decline of ⱖ 50% in at least seven of 35 patients. Per an attained phase II design, more than
`35 patients could be enrolled if the primary end point was met. Secondary objectives included:
`PSA declines of ⱖ 30% and ⱖ 90%; rate of RECIST (Response Evaluation Criteria in Solid Tumors)
`responses and duration on study; time to PSA progression; safety and tolerability; and circulating
`tumor cell (CTC) enumeration.
`Results
`Docetaxel-treated patients with CRPC (N ⫽ 47) were enrolled. PSA declines of ⱖ 30%, ⱖ 50%
`and ⱖ 90% were seen in 68% (32 of 47), 51% (24 of 47), and 15% (seven of 47) of patients,
`respectively. Partial responses (by RECIST) were reported in eight (27%) of 30 patients with
`measurable disease. Median time to PSA progression was 169 days (95% CI, 113 to 281 days).
`The median number of weeks on study was 24, and 12 (25.5%) of 47 patients remained on
`study ⱖ 48 weeks. CTCs were enumerated in 34 patients; 27 (79%) of 34 patients had at least five
`CTCs at baseline. Eleven (41%) of 27 patients had a decline from at least five to less than 5 CTCs,
`and 18 (67%) of 27 had a ⱖ 30% decline in CTCs after starting treatment with abiraterone acetate.
`Abiraterone acetate was well tolerated.
`Conclusion
`Abiraterone acetate has significant antitumor activity in post-docetaxel patients with CRPC.
`Randomized, phase III trials of abiraterone acetate are underway to define the future role of
`this agent.
`
`J Clin Oncol 28:1489-1495. © 2010 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`Castration-resistant prostate cancer (CRPC) is the
`second-most common cause of cancer-related death
`in men in the developed world.1,2 Docetaxel is the
`only currently approved drug to have shown a sur-
`vival advantage in CRPC, with a median survival
`advantage of 2 to 3 months and improved quality of
`life reported.3 The continued importance of andro-
`gen receptor (AR) activation and signaling in CRPC
`is increasingly recognized.4-6 AR-activating ligands
`
`originating in the adrenal glands or occurring by de
`novo synthesis may be activating CRPC.7-10 The
`successful development of aromatase (CYP19) in-
`hibitors in breast cancer raises the question of
`whether CYP targeting may be similarly successful
`in prostate cancer (PCa).11
`The key enzyme in steroid biosynthesis leading
`to production of androgenic and estrogenic steroids
`is CYP17.12 Inhibition of CYP17 results in decreased
`levels of downstream androgens and reduced pe-
`ripheral conversion to the more potent androgens
`
`© 2010 by American Society of Clinical Oncology
`
`1489
`
`From the Royal Marsden NHS Foundation
`Trust and The Institute of Cancer
`Research, Sutton, Surrey, United Kingdom;
`Genitourinary Oncology Service, Depart-
`ment of Medicine, Sidney Kimmel Center
`for Prostate and Urologic Cancers, Memo-
`rial Sloan-Kettering Cancer Center, New
`York, NY; University of Twente, Depart-
`ment of Medical Cell BioPhysics,
`Enschede, the Netherlands; and Cougar
`Biotechnology, Los Angeles; and Depart-
`ment of Medicine, University of California,
`San Francisco, CA.
`
`Submitted June 23, 2009; accepted Octo-
`ber 27, 2009; published online ahead of
`print at www.jco.org on February 16, 2010.
`
`Presented at the 98th Annual Meeting
`of the American Association for Cancer
`Research, April 14-18, 2007, Los Ange-
`les, CA; Annual European Society for
`Medical Oncology Conference, July 5-8,
`2007, Lugano, Switzerland; Annual
`National Cancer Research Institute
`Conference, September 30-October 3,
`2007, Birmingham, United Kingdom;
`Annual Genitourinary Meeting of the
`American Society of Clinical Oncology,
`February 14-16, 2008, San Francisco,
`CA; 44th Annual Meeting of the Ameri-
`can Society of Clinical Oncology, May
`30-June 3, 2008, Chicago, IL; and the
`45th Annual Meeting of the American
`Society of Clinical Oncology, May
`29-June 2, 2009, Orlando, FL.
`
`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: Johann S. de Bono,
`MB ChB, FRCP, MSc, PhD, The Institute
`of Cancer Research, The Royal Marsden
`NHS Foundation Trust, Downs Rd Sutton,
`Surrey SM2 5PT, United Kingdom; e-mail:
`johann.de-bono@icr.ac.uk.
`
`© 2010 by American Society of Clinical
`Oncology
`
`0732-183X/10/2809-1489/$20.00
`
`DOI: 10.1200/JCO.2009.24.6819
`
`Downloaded from ascopubs.org by 199.19.250.89 on December 20, 2016 from 199.019.250.089
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1096 PAGE 1
`
`

`

`Reid et al
`
`testosterone and dihydrotestosterone capable of AR activation. Estro-
`gens also are decreased, which may be important, as there is increasing
`evidence that they may increase the expression of hormone-regulated
`oncogenic ETS fusion genes.13
`Abiraterone (CB7598) is an oral, potent, selective, and irre-
`versible inhibitor of CYP17 that is 10- to 30-fold more potent
`than the nonselective inhibitor, ketoconazole. The parent drug
`has poor bioavailability; therefore, a prodrug was generated.14,15
`The 3-␤-O-acetate prodrug (ie, abiraterone acetate, CB7630) is rap-
`idly deacetylated to the active metabolite in vivo.14,15 In our recent,
`first-in-man, phase I evaluation of continuous daily abiraterone in
`chemotherapy-naïve men, no dose-limiting toxicities were observed,
`and—significantly—abiraterone acetate was well tolerated; moreover,
`abiraterone was active at all doses tested, as evidenced by prostate-
`specific antigen (PSA) declines, disease regression in both soft tissue
`and bone, and symptomatic improvements.5 This study reported that
`castrate, but detectable, testosterone levels at baseline declined rapidly
`to less than 1 ng/dL after treatment with abiraterone acetate.5 Com-
`patible with complete CYP17 inhibition, treatment with abiraterone
`acetate also decreases estradiol, dehydroepiandrostenedione (DHEA),
`and androstenedione. Increases in steroids upstream of CYP17, corti-
`costerone and deoxycorticosterone, reached a plateau at doses greater
`than 750 mg. A 1,000-mg dose, therefore, was selected for phase II
`evaluation. Pharmacokinetic testing confirmed a once-daily dosing
`schedule. Our phase II study in men who have not yet received chem-
`otherapy has confirmed that abiraterone is well tolerated and active in
`this setting.4
`As AR activation and signalling remain key targets in later stages
`of the disease, we hypothesized that postdocetaxel patients would
`derive benefit from abiraterone acetate. Therefore, we conducted a
`phase II study to evaluate the antitumor activity of abiraterone acetate
`1,000 mg administered daily, continuously, to castrate men with
`CRPC who had previously received docetaxel.
`
`PATIENTS AND METHODS
`
`Patient Population
`This was a multicenter, phase II study (COU-AA-003) conducted at the
`Royal Marsden NHS Foundation Trust, Memorial Sloan-Kettering Cancer
`Center, and the University of California, San Francisco, Comprehensive Can-
`cer Center. Castrate (ie, serum testosterone ⬍ 50 ng/dL, ⬍ 2.0 nmol/L)
`patients with Eastern Cooperative Oncology Group (ECOG) performance
`status (PS) 0 to 2 who had a histologic diagnosis of prostate adenocarcinoma,
`a PSA greater than 5 ng/mL, and progressive disease as defined by PSA Work-
`ing Group (PSAWG)16 criteria were eligible. Patients were permitted to be on
`stable low doses of steroids if the steroids were required to maintain fitness for
`the study. Patients were required to have a minimum washout period of 4
`weeks after the use of PCa therapy (except for luteinizing hormone-releasing
`hormone [LHRH] agonists) and were required to have 6 weeks of washout
`after antiandrogens were stopped. Patients were required to have received
`prior docetaxel chemotherapy for PCa. Other eligibility criteria included nor-
`mal serum potassium and adequate bone marrow, renal, and hepatic func-
`tions. Patients were excluded if they had brain metastases or spinal cord
`compression, active autoimmune disease that required 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 institutional
`ethics review committees of all participating centers and was conducted in
`accordance with the Declaration of Helsinki and International Conference
`on Harmonisation/WHO Good Clinical Practice standards. Written in-
`
`formed consent was obtained from all patients before any study procedures
`were performed.
`
`Study Design and Response Assessment
`This was a single-arm, open-label, two-stage, phase II study. The primary
`objective of the study was to evaluate the antitumor activity of abiraterone
`acetate in patients with CRPC who had received prior docetaxel chemothera-
`py, and the primary end point was measured by the proportion of patients
`
`Table 1. Baseline Demographic and Clinical Characteristics
`
`Characteristic
`
`Age, years
`Median
`Range
`Gleason score
`⬍ 6
`6-7
`8-9
`10
`Unknown
`Baseline PSA, ng/mL
`Median
`Range
`ECOG performance status
`0
`1
`2
`Hemoglobin, g/dL
`Median
`Range
`Albumin, g/L
`Median
`Range
`Alkaline phosphatase, ␮/L
`Median
`Range
`Predominant metastases
`Bone only
`Visceral only
`Soft tissue only
`Bone and soft tissue
`Bone and visceral
`Soft tissue and visceral
`Bone, soft tissue, and visceral
`Prior hormone therapies
`LHRH analogues
`Antiandrogens
`Steroids
`Estrogens
`Ketoconazole
`Prior chemotherapy
`Docetaxel
`Vinorelbine
`ECarboF
`Mitoxantrone
`Cyclophosphamide
`Carboplatin
`Estramustine
`Paclitaxel
`
`No. of Patients
`
`67
`48-87
`
`4
`20
`17
`1
`5
`
`403
`9.9-10,325
`
`16
`27
`4
`
`11.8
`9.4-14.6
`
`36
`23-46
`
`185
`34-110
`
`4
`0
`1
`33
`1
`1
`7
`
`47
`46
`27
`17
`8
`
`47
`3
`1
`8
`2
`2
`2
`2
`
`Abbreviations: PSA, prostate specific antigen; ECOG, Eastern Cooperative
`Oncology Group; LHRH, luteinizing hormone-releasing hormone; ECarboF,
`carboplatin plus fluorouracil plus epirubicin.
`
`1490
`
`© 2010 by American Society of Clinical Oncology
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`Downloaded from ascopubs.org by 199.19.250.89 on December 20, 2016 from 199.019.250.089
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1096 PAGE 2
`
`

`

`Post-Docetaxel Phase II Trial of Abiraterone Acetate
`
`achieving a PSA decline of ⱖ 50% from baseline, as recommended by PSAWG
`criteria.16 A confirmatory PSA value decline was obtained ⱖ 4 weeks later. For
`patients with a ⱖ 50% PSA decline from baseline, PSA progression was defined
`as an increase in PSA of 50% (minimum, 5 ng/mL) greater than nadir value
`and was confirmed by a second reading ⱖ 4 weeks later. For patients without
`a ⱖ 50% PSA decline from baseline, PSA progression was defined as an
`increase in PSA of 25% (minimum, 5 ng/mL) greater than nadir and was
`confirmed by a second reading a minimum of 4 weeks later (according to
`PSAWG). After this study was written, revised criteria for assessing re-
`sponse in prostate clinical trials has been published (ie, Prostate Cancer
`Clinical Trials Working Group) that recommends the reporting of the
`maximal PSA decline from baseline at 12 weeks and at any point on
`study.17 Measurable disease response rate, at least 3 months after the start
`of treatment per investigator’s assessment using Response Evaluation Cri-
`teria in Solid Tumors (RECIST), was reported. As conducted in our pre-
`vious chemotherapy-naı¨ve studies, ⱖ 30% and ⱖ 90% declines in PSA
`were also reported. The median time to PSA progression was defined
`according to the PSAWG criteria. Patients with PSA progression but stable
`measurable disease by RECIST and no symptoms of clinical progression
`were allowed to continue abiraterone acetate therapy and duration on
`study is therefore also reported.
`
`Treatment and Procedures
`Four capsules (250 mg each) of abiraterone acetate powder were admin-
`istered once daily, continuously, to patients in a fasted state in 28-day cycles. All
`patients underwent a history, physical exam, and safety evaluations that in-
`cluded hematology, coagulation, biochemistry, liver and renal function studies
`at baseline after the first week and at 4-week intervals. PSA, alkaline phospha-
`tase, and albumin levels were also measured. Adverse events were graded
`according to the National Cancer Institute Common Toxicity Criteria for
`Adverse Events, version 3.0. Expected toxicities of hypertension, hypoka-
`lemia, and fluid retention arising from a syndrome of secondary mineralo-
`corticoid excess were managed with either a mineralocorticoid receptor
`
`antagonist (eplerenone 50 to 200 mg) or low-dose glucocorticoids. Base-
`line high-resolution computed tomography (CT) scans and bone scans
`were performed and repeated at 3-month and 6-month intervals, respec-
`tively. Patients were offered to sign an optional secondary protocol to have
`blood samples (7.5 mL) collected into CellSave tubes (Veridex LLC, Rari-
`tan, NJ) at baseline and every 4 weeks thereafter for the enumeration of
`CTC by using the CellSearch system (Veridex), as described previously.18
`Fluorescent in situ hybridization to investigate ERG gene status was per-
`formed on CTCs, as described previously.19,20
`
`Statistical Analyses
`The primary objective was to determine the rate of patients that demon-
`strated a ⱖ 50% decline in PSA. A two-stage, Green and Dahlberg, attained-
`phase II trial design was utilized that permitted additional patients to be
`recruited if sufficient activity was demonstrated in the second stage.21 By using
`a response rate of ⱕ 10% for the null hypothesis versus an alternative hypoth-
`esis response rate of ⱖ 30%, 20 patients were to be recruited to the first stage.
`If at least three of 20 patients had a PSA decline by ⱖ 50%, the study would
`proceed to the second stage, with an additional 13 patients recruited. The null
`hypothesis would be rejected if there were at least seven patients who had a PSA
`decline by ⱖ 50% (␣⫽ .05; ␤⫽ .01). As defined a priori in the trial protocol,
`all patients treated were included in the assessment of antitumor activity.
`Patients with at least five CTCs per 7.5mL at baseline were reported as to
`whether they had a decrease in CTC to less than five CTCs; a decrease by 50%;
`or a decrease by 30%.22-24
`
`RESULTS
`
`Patient Characteristics
`Forty-seven patients were enrolled from December 2006 to
`August 2007. Table 1 lists the patient demographic and clinical
`
`90%
`50%
`30%
`
`90%
`50%
`30%
`PSA value clipped
`
`Patient
`
`Patient
`
`100
`
`50
`
`0
`
`-50
`
`-100
`
`100
`
`50
`
`0
`
`-50
`
`-100
`
`Maximal Respose (%)
`
`Week 12 PSA Response (%)
`
`A
`
`B
`
`Fig 1. Waterfall plots of prostate-specific antigen (PSA) changes. (A) Waterfall plot of greatest percentage change in PSA of individual patients on abiraterone acetate.
`(B) Waterfall plot of PSA change from baseline at 12 weeks for individual patients on abiraterone acetate. Brown, gold and gray lines indicate a decline in PSA of 30%,
`50% and 90%, respectively. Some patients had a PSA decline on study but this was short-lived; PSA then increased again, which explains why the week-12 and
`maximal PSA declines are different.
`
`www.jco.org
`
`© 2010 by American Society of Clinical Oncology
`
`1491
`
`Downloaded from ascopubs.org by 199.19.250.89 on December 20, 2016 from 199.019.250.089
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1096 PAGE 3
`
`

`

`Reid et al
`
`characteristics. Median age was 67 years (range, 48 to 87 years). All
`patients had experienced progression on LHRH agonists, and 46
`patients had received prior antiandrogens. The median numbers of
`prior hormonal therapies and prior chemotherapy agents were
`four and one, respectively. All patients had previously received
`steroid therapy with docetaxel; 27 (57%) of 47 patients also had
`received single-agent steroid treatment (ie, prednisone, dexameth-
`asone, or hydrocortisone), and 17 (36%) of 47 patients had re-
`ceived prior estrogens as well. Eight (17%) of 47 patients had
`received prior ketoconazole. Eighteen of 47 patients started the
`study on a stable dose of steroids to maintain PS. The median
`baseline PSA was 403 ng/mL (range, 9.9 to 10,325 ng/mL). Sixty-
`two percent of patients had an albumin of ⱕ 35 or 3.5 g/dL. Thirty
`patients had measurable disease on baseline CT scan. Overall, 45 of
`47 patients had evidence of bony metastases at baseline. Twenty-
`seven (79%) of 34 patients (who were in a seperate CTC acquisition
`protocol) had at least five CTCs at baseline; the median CTC count
`in the 27 patients with at least five CTCs at baseline was 36 (range,
`five to 1,712). Among patients with a CTC count of at least five at
`baseline, 14 (52%) of 27 patients had a count of five to 50 cells, and
`13 (48%) of 27 patients had a CTC count of greater than 50.
`
`47 patients and seven (15%) of 47 patients had ⱖ 30% and ⱖ 90%
`declines in PSA, respectively. These responses were confirmed at least
`4 weeks later with a second PSA except for 3 and 4 patients with PSA
`declines of ⱖ 50% and ⱖ 30% respectively for whom a confirmatory
`PSA four weeks later was not available. The percentage of change in
`PSA from baseline to 12 weeks and the maximum decline in PSA at
`any point on study are depicted for each patient in waterfall plots (Fig
`1).17 Thirty patients had measurable disease at baseline, and eight
`(27%) of 30 patients met the criteria for partial response (PR) by
`RECIST per investigator’s assessment (Fig 2).
`
`Symptomatic Improvements
`At baseline, 16 patients had an ECOG PS of 0; 27 patients had an
`ECOG PS of 1; and four patients had an ECOG PS of 2. An improvement
`in performance status was observed during treatment in 11 patients: 10
`patients shifted from ECOG 1 to ECOG 0, and one patient shifted from
`ECOG 2 to ECOG 1. ECOG PS did not change from baseline after
`treatment in 35 patients, as ECOG PS scores of 0, 1, and 2 remained
`unchanged in 15 of 16, 17 of 27, and three of four patients, respectively.
`
`Antitumor Activity: PSA Changes and Measurable
`Disease Responses
`A PSA decline of ⱖ 50% from the start of treatment was observed
`in 24 (51%) of 47 patients at least once on study. Thirty-two (68%) of
`
`Time to PSA Progression and Duration on Study
`The median time to PSA progression was 169 days (ie, 24 weeks;
`95% CI, 113 to 281 days; Fig 3). Five (10.6%) of 47 patients were on
`study fewer than 12 weeks; 18 (38.3%) of 47 patients were on study for
`12 to 23 weeks; 12 (25.5%) of 47 patients were on study 24 to 47 weeks;
`
`A
`
`C
`
`B
`
`D
`
`2C
`E
`
`2D
`F
`
`Fig 2. Radiologic responses. (A) Patient 010 had previously experienced progression on an luteinizing hormone-releasing hormone (LHRH) agonist, flutamide,
`bicalutamide, docetaxel, the monoclonal antibody to IGF-1R, CP-751, 871, and the survivin inhibitor YM155. Before starting treatment with abiraterone acetate, the
`prostate-specific antigen (PSA) was 789, and there was evidence of nodal and bony metastatic disease. Circulating tumor cells (CTCs) were not detected. Red oval,
`retroperitoneal nodal disease on a baseline computed tomography (CT) scan (A). After 3 months on abiraterone acetate, PSA decreased to a nadir of 1.4 (ie, ⬎ 90%
`decline), and (B) the red oval shows that the nodal disease has largely disappeared. Patient 010 continues to take study drug, now in the third year of treatment. (C)
`Patient 025 had previously experienced progression on an LHRH agonist, antiandrogen, stilboestrol, and docetaxel. Baseline PSA was 10,325, and it decreased to a
`PSA nadir of 46 (ie, ⬎ 90% decline) after 4 months on abiraterone acetate. Baseline CTC count was 20, which decreased to a CTC count nadir of 0 after 4 weeks. Green
`oval, CT scan at baseline demonstrated an axillary nodal metastasis (C). Reduction in size is seen in a follow-up scan performed at 6 months (green oval; D). (E)
`Whole-body, 99mTc-MDP bone scintigraphy at baseline (again for patient 025). A response in the bony disease can be seen in (F) after 6 months on abiraterone acetate.
`This patient remained on study in excess of a year (ie, 482 days).
`
`1492
`
`© 2010 by American Society of Clinical Oncology
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`Downloaded from ascopubs.org by 199.19.250.89 on December 20, 2016 from 199.019.250.089
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1096 PAGE 4
`
`

`

`Post-Docetaxel Phase II Trial of Abiraterone Acetate
`
`Median (days) 169 (95% CI, 113 to 281)
`
`Table 2. Incidence of Most Frequent Treatment-Related Adverse Events
`
`Patients by Event Grade (N ⫽ 47)
`
`Grade 1
`
`Grade 2
`
`Grade 3
`
`Grade 4
`
`Event
`
`No. % No. % No. % No. %
`
`Nausea
`Constipation
`Fatigue
`Peripheral edema
`Hypokalaemia
`Anorexia
`Hyperglycemia
`Headache
`Hypertension
`
`3
`1
`2
`2
`25
`4
`1
`3
`3
`
`6
`2
`4
`4
`53
`9
`2
`6
`6
`
`2
`4
`10
`5
`0
`4
`5
`2
`5
`
`4
`9
`21
`11
`
`9
`11
`4
`11
`
`2
`0
`3
`0
`1
`1
`0
`0
`0
`
`4
`
`6
`
`2
`2
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`1
`
`0.75
`
`0.5
`
`0.25
`
`Probability
`
`Censored
`
`0
`
`40 100 160 220 280 340 400 460 520 580 640 700 760 820
`Study Day
`
`Fig 3. Time to prostate-specific antigen (PSA) progression. Median time to PSA
`progression is 169 days (95% CI, 113 to 281 days).
`
`NOTE. Treatment-related effects from abiraterone acetate or steroid treatment.
`Only events occurring in ⱖ 10% of patients are reported in this Table. One patient
`reported grade 4 increase in transaminases not shown in the Table.
`
`Safety
`All 47 patients were evaluable for adverse events. Abiraterone
`acetate was, in general, well tolerated. The expected and related toxic-
`ities of hypokalemia, hypertension, and fluid retention occurred in 26
`(55%), eight (17%), and seven (15%) patients, respectively, and were
`easily managed (eplerenone/low-dose glucocorticoids). Three deaths
`occurred on study. One patient developed pneumonia, and another
`patient developed progressive disease and deteriorated rapidly. Nei-
`ther of these deaths was considered related to study drug. The third
`patient, who had diabetes and a cardiac history, was admitted to
`hospital with groin pain at the site of extensive bony metastases.
`During the admission, he experienced chest discomfort and was
`treated for a possible upper respiratory tract infection. He had an
`asystolic cardiac arrest attributed to a myocardial infarct or pulmo-
`nary embolus. A postmortem was not conducted. Table 2 lists ad-
`verse events.
`
`DISCUSSION
`
`This study in patients with late-stage metastatic CRPC who have
`received prior docetaxel treatment demonstrates that selective, irre-
`versible CYP17 inhibition with abiraterone acetate results in signifi-
`cant antitumor activity. The antitumor activity is in keeping with levels
`reported in our chemotherapy-naı¨ve studies4,5 and by Ryan et al25 in
`this issue of Journal of Clinical Oncology (JCO). Declines in PSA of
`ⱖ 50% were seen in 51% of patients. PSA declines were supported by
`radiologic responses, improvement in symptoms, and CTC declines.
`Similar activity in this patient population is reported by Danila et al26
`in this issue of JCO. Overall, these results suggest that a significant
`proportion of CRPC remains hormone driven after docetaxel treat-
`ment, which supports therapeutic targeting of the AR and AR signal-
`ing in this population. These data led to the development of an 1,158
`patient registration phase III trial of prednisone with either abi-
`raterone acetate or placebo in a 2:1 random assignment in docetaxel-
`treated patients, for which overall survival was the primary end point
`(ie, NCT00638690). The CTC data in this phase II study led to the
`incorporation of CTC count evaluation into the phase III trial to
`establish whether the impact of treatment on CTC count can serve as
`
`and 12 (25.5%) of 47 patients remained on study at least 48 weeks. At the
`time of data cutoff (ie, May 2009), five patients continued on abiraterone
`acetate (⫹913, ⫹886, ⫹795, ⫹726, ⫹698 days, respectively).
`
`Declines in CTC Count
`After treatment with abiraterone acetate was started, 11 (41%) of
`27 patients had a decline in CTC count from five or greater to less than
`five. Seventeen (63%) of 27 patients had a decline in CTC count by
`ⱖ 50%, and 18 (67%) of 27 patients had a decline in CTC count
`by ⱖ 30% after starting treatment with abiraterone acetate. CTC
`count declines from five or greater to less than 5 and declines of 50%
`and 30% have been associated previously with improved overall
`survival.22-24 One of 27 patients with a CTC count of ⱖ 5 only had a
`baseline reading. A waterfall plot of maximal percentage CTC count
`decline on abiraterone acetate is shown in Figure 4. Maximal change in
`CTC count did not correlate with maximal PSA change (r ⫽ 0.093;
`P ⫽ .762 by Pearson Rho test) in the population as a whole. However,
`for patients with ERG gene–rearranged tumors, PSA and CTC count
`declines were significantly correlated (r⫽ 0.762; P ⫽ .001); conversely,
`PSA and CTC count declines were not correlated for patients with
`ERG gene–unrearranged disease (r ⫽ 0.493; P ⫽ .010; Appendix Fig
`A1, online only).
`
`Patients
`
`20
`10
`0
`-10
`-20
`-30
`-40
`-50
`-60
`-70
`-80
`-90
`-100
`
`Maximal CTC Change (%)
`
`Fig 4. Waterfall plot of maximal circulating tumor cell (CTC) count declines in
`individual patients on abiraterone acetate. Twenty-six patients are featured in the
`plot as 1/27 patients with ⱖ 5 CTCs only had a baseline measurement. Brown,
`gold and gray lines indicate a decline in CTC count of 30%, 50% and 90%
`respectively. Red dots indicate clipped CTC count values.
`
`www.jco.org
`
`© 2010 by American Society of Clinical Oncology
`
`1493
`
`Downloaded from ascopubs.org by 199.19.250.89 on December 20, 2016 from 199.019.250.089
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1096 PAGE 5
`
`

`

`Reid et al
`
`an intermediate end point of overall survival in CRPC. Concordance
`was seen between PSA and CTC for patients with ERG gene–rear-
`ranged disease but not for patients without an ERG gene rearrange-
`ment. As ERG gene rearrangements and PSA production are hormone
`regulated, one might expect that PSA should more accurately reflect a
`therapeutic effect and be concordant with CTC counts in the patients
`with ERG gene–rearranged disease. These data, albeit preliminary and
`in small numbers, are in keeping with the mechanism of action of
`abiraterone acetate.
`The patients recruited to this study had many poor prognostic
`features, including the following: albumin ⱕ 35 or 3.5 g/dL (62%);
`PS of ⱖ 1 (66%); and CTC count of at least five (79%).22-24,27 All of
`these patients had disease that was resistant to most standard and
`some experimental lines of therapy. Specifically, all patients had re-
`ceived docetaxel, the only agent to have shown a survival benefit in
`this group.3
`Importantly, despite the more advanced stage of the disease and
`the poorer patient PS, the adverse events seen in these post-docetaxel
`patients were similar to those in our recently reported phase I and II
`pre-docetaxel studies (N ⫽ 54 patients) of abiraterone acetate.4,5 As
`reported in our previous phase I experience, no hypoadrenalism was
`seen. Hypokalemia, hypertension, and fluid retention—all expected
`toxicities that occur because of increased adrenocorticotrophic hor-
`mone and a resultant excess of mineralocorticoid steroids upstream of
`CYP17—were effectively managed with a mineralocorticoid receptor
`antagonist or a low-dose of glucocorticoid.
`This study provides additional evidence that selective CYP17
`inhibition with abiraterone acetate in postdocetaxel patients with
`CRPC is well tolerated and has significant antitumor activity. These
`results highlight the continued importance of the AR axis, even in the
`most advanced stages of the disease, and warrant phase III confirmation.
`
`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: Alison H.M. Reid, Cougar Biotechnology
`(U); Gerhardt Attard, Cougar Biotechnology (U); Daniel C. Danila,
`Cougar Biotechnology (U); Leon W.M.M. Terstappen, Veridex (C); Eric
`Small, Cougar Biotechnology (C); Howard I. Scher, Cougar
`Biotechnology (C), Veridex LLC (U); Johann S. de Bono, Cougar
`Biotecnology (U) Stock Ownership: Thian Kheoh, Cougar
`Biotechnology; Arturo Molina, Cougar Biotechnology Honoraria: None
`Research Funding: Howard I. Scher, Veridex, Cougar Biotechnology
`Expert Testimony: None Other Remuneration: None
`
`AUTHOR CONTRIBUTIONS
`
`Conception and design: Alison H.M. Reid, Johann S. de Bono
`Financial support: Arturo Molina
`Administrative support: Gloria Lee, Thian Kheoh, Arturo Molina
`Provision of study materials or patients: Alison H.M. Reid, Gerhardt
`Attard, Daniel C. Danila, Nikhil Babu Oommen, David Olmos, Peter C.
`Fong, L. Rhoda Molife, Joanne Hunt, Christopher Parker, David Dearnaley,
`Charles J. Ryan, Eric Small, Howard I. Scher, Johann S. de Bono
`Collection and assembly of data: Alison H.M. Reid, Gerhardt Attard,
`Daniel C. Danila, Nikhil Babu Oommen, David Olmos, Peter C. Fong, L.
`Rhoda Molife, Joanne Hunt, Christina Messiou, Joost F. Swennenhuis, Leon
`W.M.M. Terstappen, Thian Kheoh, Charles J. Ryan, Johann S. de Bono
`Data analysis and interpretation: Alison H.M. Reid, David Olmos,
`Thian Kheoh, Johann S. de Bono
`Manuscript writing: Alison H.M. Reid, Johann S. de Bono
`Final approval of manuscript: Alison H.M. Reid, Gerhardt Attard,
`Daniel C. Danila, Nikhil Babu Oommen, David Olmos, Peter C. Fong, L.
`Rhoda Molife, Joanne Hunt, Christina Messiou, Christopher Parker,
`David Dearnaley, Joost F. Swennenhuis, Leon W.M.M. Terstappen,
`Gloria Lee, Thian Kheoh, Arturo Molina, Charles J. Ryan, Eric Small,
`Howard I. Scher, Johann S. de Bono
`
`REFERENCES
`
`1. National Cancer Institute: Surveillance, Epide-
`miology and End Results. www.seer.cancer.gov
`2. Ferlay J, Autier P, Boniol M, et al: Estimates
`of the cancer incidence and mortality in Europe in
`2006. Ann Oncol 18:581-592, 2007
`3. Tannock IF, de Wit R, Berry WR, et al: Do-
`cetaxel plus prednisone or mitoxantrone plus pred-
`nisone for advanced prostate cancer. N Engl J Med
`351:1502-1512, 2004
`4. Attard G, Reid AH, A’Hern R, et al: Selective
`inhibition of CYP17 with abiraterone acetate is
`highly active in the treatment of castration-resistant
`prostate cancer. J Clin Oncol 27:3742-3748, 2009
`5. Attard G, Reid AH, Yap TA, et al: Phase I
`clinical trial of a selective inhibitor of CYP17, abi-
`raterone acetate, confirms that castration-resistant
`prostate cancer commonly remains hormone driven.
`J Clin Oncol 26:4563-4571, 2008
`6. Attard G, Sarker D, Reid A, et al: Improving
`the outcome of patients with castration-resistant
`prostate cancer through rational drug development.
`Br J Cancer 95:767-774, 2006
`
`7. Holzbeierlein J, Lal P, LaTulippe E, et al: Gene
`expression analysis of human prostate carcinoma
`during hormonal
`therapy
`identifies
`androgen-
`responsive genes and mechanisms of therapy resis-
`tance. Am J Pathol 164:217-227, 2004
`8. Stanbrough M, Bubley GJ, Ross K, et al:
`Increased expression of genes converting adrenal
`androgens to testosterone in androgen-independent
`prostate cancer. Cancer Res 66:2815-2825, 2006
`9. Mohler JL, Gregory CW, Ford OH 3rd, et al:
`The androgen axis in recurrent prostate cancer. Clin
`Cancer Res 10:440-448, 2004
`10. Montgomery RB, Mostaghel EA, Vessella R,
`et al: Maintenance of intratumoral androgens in
`meta