The new england
`journal of medicine
`
`established in 1812
`
`may 26, 2011
`Abiraterone and Increased Survival in Metastatic Prostate Cancer
`
`vol. 364 no. 21
`
`Johann S. de Bono, M.B., Ch.B., Ph.D., Christopher J. Logothetis, M.D., Arturo Molina, M.D., Karim Fizazi, M.D., Ph.D.,
`Scott North, M.D., Luis Chu, M.D., Kim N. Chi, M.D., Robert J. Jones, M.D., Oscar B. Goodman, Jr., M.D., Ph.D.,
`Fred Saad, M.D., John N. Staffurth, M.D., Paul Mainwaring, M.D., M.B., B.S., Stephen Harland, M.D.,
`Thomas W. Flaig, M.D., Thomas E. Hutson, D.O., Pharm.D., Tina Cheng, M.D., Helen Patterson, M.D.,
`John D. Hainsworth, M.D., Charles J. Ryan, M.D., Cora N. Sternberg, M.D., Susan L. Ellard, M.D.,
`Aude Fléchon, M.D., Ph.D., Mansoor Saleh, M.D., Mark Scholz, M.D., Eleni Efstathiou, M.D., Ph.D.,
`Andrea Zivi, M.D., Diletta Bianchini, M.D., Yohann Loriot, M.D., Nicole Chieffo, M.B.A., Thian Kheoh, Ph.D.,
`Christopher M. Haqq, M.D., Ph.D., and Howard I. Scher, M.D., for the COU-AA-301 Investigators*
`
`ABS TR ACT
`
`BACKGROUND
`Biosynthesis of extragonadal androgen may contribute to the progression of cas-
`tration-resistant prostate cancer. We evaluated whether abiraterone acetate, an in-
`hibitor of androgen biosynthesis, prolongs overall survival among patients with
`metastatic castration-resistant prostate cancer who have received chemotherapy.
`
`METHODS
`We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received
`docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abi-
`raterone acetate (797 patients) or placebo (398 patients). The primary end point was
`overall survival. The secondary end points included time to prostate-specific anti-
`gen (PSA) progression (elevation in the PSA level according to prespecified criteria),
`progression-free survival according to radiologic findings based on prespecified cri-
`teria, and the PSA response rate.
`
`RESULTS
`After a median follow-up of 12.8 months, overall survival was longer in the abiraterone
`acetate–prednisone group than in the placebo–prednisone group (14.8 months vs.
`10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001).
`Data were unblinded at the interim analysis, since these results exceeded the pre-
`planned criteria for study termination. All secondary end points, including time to
`PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months
`vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the
`treatment group. Mineralocorticoid-related adverse events, including fluid reten-
`tion, hypertension, and hypokalemia, were more frequently reported in the abi-
`raterone acetate–prednisone group than in the placebo–prednisone group.
`
`CONCLUSIONS
`The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall
`survival among patients with metastatic castration-resistant prostate cancer who
`previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301
`ClinicalTrials.gov number, NCT00638690.)
`
`n engl j med 364;21 nejm.org may 26, 2011
`
`From the Institute of Cancer Research and
`Royal Marsden Hospital, Sutton (J.S.B.,
`A.Z., D.B.), Institute of Cancer Sciences,
`Glasgow (R.J.J.), Cardiff University, Velindre
`Hospital, Cardiff (J.N.S.), and Cambridge
`(H.P.) — all in the United Kingdom; M.D. An-
`derson Cancer Center, Houston (C.J.L., E.E.);
`Ortho Biotech Oncology Research and Devel-
`opment (a unit of Cougar Biotechnology), Los
`Angeles (A.M., N.C., T.K., C.M.H.); Institut
`Gustave Roussy, Villejuif (K.F., Y.L.), and Cen-
`tre Léon Bérard, Lyon (A.F.) — both in France;
`Cross Cancer Institute, Edmonton, AB (S.N.),
`BC Cancer Agency, Vancouver Cancer Centre,
`Vancouver (K.N.C.), University of Calgary,
`Calgary, AB (T.C.), and BC Cancer Agency,
`Centre for the Southern Interior, Kelowna
`(S.L.E.) — all in Canada; Oncology Hematol-
`ogy Consultants, Sarasota, FL (L.C.); Nevada
`Cancer Institute, Las Vegas (O.B.G.); Univer-
`sity of Montreal, Montreal (F.S.); Haematol-
`ogy and Oncology Clinics of Australasia,
`Milton, Australia (P.M.); UCL Cancer Insti-
`tute, London (S.H.); University of Colorado
`Cancer Center, Aurora (T.W.F.); Texas Oncol-
`ogy–Baylor Charles A. Sammons Cancer Cen-
`ter, Dallas (T.E.H.); Sarah Cannon Research
`Institute, Nashville (J.D.H.); Helen Diller
`Family Comprehensive Cancer Center, Uni-
`versity of California–San Francisco, San
`Francisco (C.J.R.); San Camillo and Forlanini
`Hospitals, Rome (C.N.S.); Georgia Cancer
`Specialists, Atlanta (M. Saleh); Prostate
`Oncology Specialists, Marina del Rey, CA (M.
`Scholz); and Memorial Sloan-Kettering Can-
`cer Center, and Weill Cornell Medical Col-
`lege, New York (H.I.S.). Address reprint re-
`quests to Dr. de Bono at the Institute of
`Cancer Research and Royal Marsden Hospi-
`tal, Downs Rd., Sutton, Surrey SM2 5PT, Unit-
`ed Kingdom, or at johann.de-bono@icr.ac.uk.
`* Additional COU-AA-301 investigators are
`listed in the Supplementary Appendix,
`available at NEJM.org.
`N Engl J Med 2011;364:1995-2005.
`Copyright © 2011 Massachusetts Medical Society.
`1995
`
`The New England Journal of Medicine
`Downloaded from nejm.org on September 28, 2015. For personal use only. No other uses without permission.
` Copyright © 2011 Massachusetts Medical Society. All rights reserved.
`
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`

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`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`For the past 70 years, depleting or
`
`blocking the action of androgens has been
`the standard of care for men with advanced
`prostate cancer.1 Androgen deprivation results in a
`decrease in the concentration of prostate-specific
`antigen (PSA) as well as tumor regression and re-
`lief of symptoms in most patients, but the response
`to treatment is not durable in patients with ad-
`vanced cancer, and with time, PSA concentrations
`increase, indicating reactivated androgen-receptor
`signaling and a transition to a castration-resistant
`state that is invariably fatal.2 Many endocrine ther-
`apies have been evaluated in these patients, but
`none have prolonged survival.3 Three nonhormonal
`systemic approaches have been found to prolong
`survival: docetaxel4 as first-line and cabazitaxel5 as
`second-line cytotoxic chemotherapy, and active cel-
`lular immunotherapy with sipuleucel-T.6
`A unique molecular alteration described in
`castration-resistant prostate cancer is the up-regu-
`lation of androgen biosynthesis enzymes, leading
`to an increase in intratumoral androgen concen-
`trations, which can exceed the levels measured in
`the blood.7-9 Other alterations include overexpres-
`sion of androgen receptors, and androgen-receptor
`mutations leading to androgen-receptor binding
`by additional ligands that would not stimulate the
`wild-type receptor.2,10 Abiraterone acetate, a pro-
`drug of abiraterone, is a selective inhibitor of
`androgen biosynthesis that potently blocks cy-
`tochrome P450 c17 (CYP17), a critical enzyme in
`testosterone synthesis, thereby blocking androgen
`synthesis by the adrenal glands and testes and
`within the prostate tumor.11-14 In phase 1–2 trials,
`treatment with abiraterone acetate, either as a sin-
`gle agent or in combination with low-dose gluco-
`corticoids such as prednisone, resulted in signifi-
`cant antitumor activity among both patients with
`progressing castration-resistant prostate cancer
`who had not received chemotherapy and those who
`had received chemotherapy.15-20 The most com-
`mon adverse events, which were associated with
`increased mineralocorticoid levels, included hypo-
`kalemia, fluid retention, and hypertension; these
`events were largely abrogated by coadministering
`low-dose glucocorticoids. We hypothesized that
`inhibition of androgen biosynthesis with abira-
`terone acetate and prednisone would improve
`overall survival among patients with advanced
`prostate cancer.
`
`Methods
`
`Patients
`Patients were eligible to participate in the study
`if they had histologically or cytologically con-
`firmed prostate cancer that had previously been
`treated with docetaxel, disease progression ac-
`cording to the criteria of the Prostate Cancer
`Working Group21,22 (for trial entry, patients were
`considered to have disease progression if they
`had two consecutive increases in the PSA concen-
`tration over a reference value) or radiographic evi-
`dence of disease progression in soft tissue or bone
`with or without disease progression on the basis
`of the PSA value, and ongoing androgen depriva-
`tion, with a serum testosterone level of 50 ng per
`deciliter or less (≤2.0 nmol per liter).
`Additional eligibility criteria included an East-
`ern Cooperative Oncology Group (ECOG)23 per-
`formance status score of 2 or less (on a scale from
`0 to 5, with 0 indicating that the patient is fully
`active and able to carry on all predisease activities
`without restriction; 1 indicating that the patient
`is restricted in physically strenuous activity but is
`ambulatory and able to carry out work of a light
`or sedentary nature, such as light housework or
`office work; and 2 indicating that the patient is
`ambulatory and up and about more than 50% of
`waking hours and is capable of all self-care but
`unable to carry out any work activities) and hema-
`tologic and chemical laboratory values that met
`predefined criteria, including an albumin level of
`3.0 g per deciliter or higher.
`Patients were excluded if they had abnormal
`aminotransferase levels (levels of aspartate amino-
`transferase or alanine aminotransferase that were
`≥2.5 times the upper level of the normal range;
`patients with known liver metastasis who had lev-
`els of aspartate aminotransferase or alanine ami-
`notransferase that were ≤5 times the upper level
`of the normal range were eligible to participate),
`serious coexisting nonmalignant disease, active or
`symptomatic viral hepatitis or chronic liver dis-
`ease, uncontrolled hypertension, a history of pitu-
`itary or adrenal dysfunction, clinically significant
`heart disease, or previous therapy with ketocon-
`azole.
`The review boards at all participating institu-
`tions approved the study, which was conducted
`according to the Declaration of Helsinki and the
`
`1996
`
`n engl j med 364;21 nejm.org may 26, 2011
`
`The New England Journal of Medicine
`Downloaded from nejm.org on September 28, 2015. For personal use only. No other uses without permission.
` Copyright © 2011 Massachusetts Medical Society. All rights reserved.
`
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`Abiraterone and Survival in Metastatic Prostate Cancer
`
`Good Clinical Practice guidelines of the Interna-
`tional Conference on Harmonization. All patients
`provided written informed consent to participate
`in the study.
`
`Study Design and Treatment
`This phase 3, multinational, randomized, double-
`blind, placebo-controlled study was conducted at
`147 sites in 13 countries. Patients were enrolled
`from May 2008 through July 2009 and were strat-
`ified according to baseline ECOG performance
`status score (0 or 1 vs. 2), level of worst pain over
`the previous 24 hours on the Brief Pain Invento-
`ry–Short Form (BPI-SF) (on a scale of 0 to 10,
`with 0 to 3 indicating that clinically significant
`pain is absent vs. 4 to 10 indicating that clini-
`cally significant pain is present),24,25 number of
`previous chemotherapy regimens (one vs. two),
`and type of evidence of disease progression (an
`increase in the PSA concentration only vs. radio-
`graphic evidence of progression with or without
`an increase in the PSA concentration). Patients
`were then randomly assigned in a 2:1 ratio to re-
`ceive either abiraterone acetate and prednisone or
`placebo and prednisone. Blocked randomization
`was used.
`Patients received 1 g of abiraterone acetate
`(administered as four 250-mg tablets) or four
`placebo tablets orally once daily at least 1 hour
`before or 2 hours after a meal, with prednisone at
`a dose of 5 mg orally twice daily. Each cycle of
`treatment was 28 days. Treatment could be con-
`tinued until disease progression was documented
`on the basis of the PSA concentration, radio-
`graphic imaging, and clinical findings. Safety and
`dosing compliance were evaluated on day 15 of
`cycle 1 and on day 1 of each subsequent cycle, at
`the time of treatment discontinuation if applica-
`ble, and at the end-of-study visit.
`The primary end point was overall survival,
`defined as the time from randomization to death
`from any cause. The prespecified secondary end
`points included the PSA response rate (defined
`as the proportion of patients with a decrease of
`≥50% in the PSA concentration from the pretreat-
`ment baseline PSA value, which was confirmed
`after ≥4 weeks by an additional PSA evaluation).
`Other secondary end points included time to PSA
`progression according to prespecified criteria
`(in patients in whom the PSA level had not de-
`
`creased, PSA progression was defined as a 25%
`increase over the baseline and an increase in the
`absolute-value PSA level by at least 5 ng per mil-
`liliter, which was confirmed by a second value; in
`patients in whom the PSA had decreased but had
`not reached response criteria [PSA ≤50%], pro-
`gressive disease would be considered to have
`occurred when the PSA level increased 25% over
`the nadir, provided that the increase was a
`minimum of 5 ng per milliliter and was con-
`firmed; and if at least a 50% decrease in the PSA
`level had been achieved, PSA progression would
`be an increase of 50% above the nadir at a
`minimum of 5 ng per milliliter), and radiograph-
`ic evidence of progression-free survival according
`to prespecified criteria (defined as soft-tissue dis-
`ease progression according to modified Response
`Evaluation Criteria in Solid Tumors [RECIST]26
`[with a baseline lymph node of ≥2.0 cm consid-
`ered to be a target lesion] or progression accord-
`ing to bone scans showing two or more new
`lesions not consistent with tumor flare). A com-
`plete response was defined as the disappearance
`of all target and nontarget lesions, and a partial
`response as a decrease by at least 30% in the sum
`of the largest diameter of each target lesion, rela-
`tive to the corresponding sum at baseline. Stable
`disease was defined as the absence of shrinkage
`sufficient for a partial response and the absence
`of enlargement sufficient for progressive disease,
`relative to the sum of the largest diameter of each
`target lesion at baseline, and progressive disease
`as an increase by at least 20% in the sum of the
`largest diameter of each target lesion, relative to
`the smallest corresponding diameter recorded
`since the start of treatment, or the appearance of
`one or more new lesions. Definitions of the
`secondary end points are provided in Table 1 in
`the Supplementary Appendix, available with the
`full text of this article at NEJM.org.
`
`Study Assessments
`Efficacy assessments included the PSA concentra-
`tion, radiographic imaging, the pain level on the
`BPI-SF, and analgesic use. Clinical assessments
`included the patient’s medical history, vital-sign
`measurements, and body weight; a physical ex-
`amination; review of concomitant therapy and
`procedures and of adverse events and serious ad-
`verse events, including adverse events detected by
`
`n engl j med 364;21 nejm.org may 26, 2011
`
`1997
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on September 28, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2011 Massachusetts Medical Society. All rights reserved.
`
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`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`means of laboratory tests; blood chemical, hema-
`tologic, coagulation, and serum lipid studies; uri-
`nalysis; electrocardiography; and measurement of
`the cardiac ejection fraction. An independent data
`and safety monitoring committee monitored pa-
`tient safety at regular intervals.
`Other assessments for analyses of exploratory
`end points included the score on the Functional
`Assessment of Cancer Therapy–Prostate question-
`naire27; the score for fatigue, as evaluated by
`means of the Brief Fatigue Inventory instrument28;
`information on medical resource utilization29; and
`counts of circulating tumor cells.30
`
`Study Oversight
`This study was designed by both the academic
`authors and employees of the sponsor, the Ortho
`Biotech Oncology Research and Development Unit
`of Cougar Biotechnology. The first draft of the
`manuscript was written by some of the academic
`authors and employees of the sponsor; the draft
`was then completed and approved by the other co-
`authors. All authors were responsible for writing
`the manuscript and for the decision to submit the
`manuscript for publication, and all authors assume
`responsibility for the completeness and integrity
`of the data. The blinded database was held at a
`third-party contract clinical research organiza-
`tion, and queries were issued by both the sponsor
`and the staff of the clinical research organization.
`The statistician employed by the independent clin-
`ical research organization provided the analysis to
`the independent data and safety monitoring com-
`mittee, whose members were invited by the spon-
`sor. After the independent data and safety moni-
`toring committee recommended unblinding of the
`data, analyses of the data were performed by a stat-
`istician employed by the sponsor, and the results
`were reviewed by the authors.
`
`Statistical Analysis
`The planned sample of approximately 1158 pa-
`tients provided 85% power to detect a hazard ratio
`of 0.80 for death in the group receiving abiraterone
`acetate plus prednisone as compared with the
`group receiving placebo plus prednisone. This
`sample size was calculated by assuming a median
`survival of 15 months for the abiraterone acetate
`group and 12 months for the placebo group, with
`a two-sided significance level (alpha) of 0.05, an
`enrollment period of approximately 13 months,
`and a total study duration of approximately 30
`months to observe the required 797 total events.
`
`One interim analysis was planned after 534 deaths
`were observed (67% of 797 total events) in a group-
`sequential design with the use of the O’Brien–
`Fleming stopping boundary. Distributions of time-
`to-event variables and associated 95% confidence
`intervals were estimated with the use of the Ka-
`plan–Meier product-limit method. The stratified
`log-rank test was used as the primary analysis for
`comparison of treatment groups. Statistical infer-
`ence was evaluated with the use of the chi-square
`statistic. Analyses of overall survival with the use
`of the nonstratified log-rank test and Cox propor-
`tional-hazards model were also performed as sup-
`portive analyses. Subgroup analyses were carried
`out to assess whether treatment effects were con-
`sistent across subgroups.
`
`R esults
`
`Patients and Treatment
`We randomly assigned 1195 patients to receive abi-
`raterone acetate plus prednisone (797 patients) or
`placebo plus prednisone (398 patients) (Fig. 1 in the
`Supplementary Appendix). Baseline demographic
`and other characteristics were well-balanced be-
`tween the two treatment groups (Table 1). Most
`patients (67%) had radiographic evidence of dis-
`ease progression before study entry. The median
`duration of treatment was 8 months in the group
`that received abiraterone acetate plus prednisone
`(hereinafter referred to as the abiraterone acetate
`group) and 4 months in the group that received
`placebo plus prednisone (hereinafter referred to
`as the placebo group). The median follow-up in
`the overall study population was 12.8 months.
`
`Efficacy
`At the time of the preplanned interim analysis,
`treatment with abiraterone acetate plus predni-
`sone resulted in a 35.4% reduction in the risk of
`death as compared with placebo plus prednisone
`(hazard ratio, 0.65; 95% confidence interval [CI],
`0.54 to 0.77; P<0.001). A total of 552 patients in the
`intention-to-treat population died: 333 patients in
`the abiraterone acetate group (42%) and 219 pa-
`tients in the placebo group (55%). The median
`overall survival was 14.8 months in the abiraterone
`acetate group and 10.9 months in the placebo
`group (Fig. 1A). The effect of abiraterone acetate
`and prednisone on overall survival was consistent
`across all subgroups (Fig. 2), and the significance
`of the treatment effect on overall survival was ro-
`bust after adjustment for stratification factors in a
`
`1998
`
`n engl j med 364;21 nejm.org may 26, 2011
`
`The New England Journal of Medicine
`Downloaded from nejm.org on September 28, 2015. For personal use only. No other uses without permission.
` Copyright © 2011 Massachusetts Medical Society. All rights reserved.
`
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`Abiraterone and Survival in Metastatic Prostate Cancer
`
`Table 1. Baseline Demographic and Clinical Characteristics of the Patients.*
`
`Characteristic
`Age
`Median (range) — yr
`
`≥75 yr — no. of patients/total no. (%)
`Disease location — no. of patients/total no. (%)
`Bone
`Node
`Liver
`BPI-SF score for pain†
`No. of patients
`Median score (range)
`No. of previous cytotoxic chemotherapy regimens —
`no. of patients/total no. (%)
`
`1
`2
`ECOG performance status — no. of patients/total no. (%)
`0 or 1
`2
`Prostate-specific antigen
`No. of patients
`
`Abiraterone Acetate
`(N = 797)
`
`Placebo
`(N = 398)
`
`69 (42–95)
`
`220/797 (28)
`
`709/797 (89)
`361/797 (45)
`90/797 (11)
`
`792
`3.0 (0–10)
`
`558/797 (70)
`239/797 (30)
`
`715/797 (90)
`82/797 (10)
`
`69 (39–90)
`
`111/397 (28)
`
`357/397 (90)
`164/397 (41)
`30/397 (8)
`
`394
`3.0 (0–10)
`
`275/398 (69)
`123/398 (31)
`
`353/398 (89)
`45/398 (11)
`
`788
`
`393
`
`Median (range) — ng/ml
`
`128.8 (0.4–9253.0)
`
`137.7 (0.6–10114.0)
`
`* See Table 2 in the Supplementary Appendix for more baseline demographic and clinical characteristics.
`† The Brief Pain Inventory–Short Form (BPI-SF) rates pain on a scale of 0 to 10, with 0 to 3 indicating that clinically sig-
`nificant pain is absent and 4 to 10 indicating that clinically significant pain is present. The scores shown are for the
`worst pain over the previous 24 hours.
`
`multivariate analysis (hazard ratio for death, 0.66;
`95% CI, 0.55 to 0.78; P<0.001) (Table 2). These data
`led the independent data and safety monitoring
`committee to recommend unblinding of the study
`data, with patients in the placebo group receiving
`abiraterone acetate if they met the criteria for
`crossover treatment specified in protocol amend-
`ment 3.0 (see the protocol, available at NEJM.org).
`All the secondary end points analyzed provided
`support for the superiority of abiraterone acetate
`over placebo (Table 3), including the confirmed
`PSA response rate (29% vs. 6%, P<0.001), the ob-
`jective response rate on the basis of RECIST among
`patients with measurable disease at baseline (14%
`vs. 3%, P<0.001), time to PSA progression (10.2
`months vs. 6.6 months), and median progression-
`free survival on the basis of radiographic evidence
`(5.6 vs. 3.6 months). On the basis of the PSA con-
`centration, abiraterone acetate was associated with
`a 42% reduction in the risk of disease progression
`(hazard ratio, 0.58; 95% CI, 0.46 to 0.73; P<0.001),
`and on the basis of radiographic imaging, it was
`
`associated with a 33% reduction in the risk of pro-
`gression (hazard ratio, 0.67; 95% CI, 0.58 to 0.78;
`P<0.001) (Table 3 and Fig. 1B and 1C).
`Evaluations of exploratory end points at the
`interim analysis also favored abiraterone acetate
`relative to placebo, including the time to 25% of
`the patients having a skeletal event (9.9 vs. 4.9
`months) and the rate of pain palliation among
`patients with a baseline pain score of 4 or more
`and at least one post-baseline pain score (44% vs.
`27%, P = 0.002). Patients in the abiraterone ace-
`tate group had consistently improved pain pal-
`liation as compared with those in the placebo
`group.
`
`Safety
`The most common adverse event was fatigue,
`which occurred at a similar frequency in the two
`treatment groups (Table 4). Other common adverse
`events in both groups were back pain (30% in the
`abiraterone acetate group and 33% in the placebo
`group), nausea (30% and 32%, respectively), consti-
`
`n engl j med 364;21 nejm.org may 26, 2011
`
`1999
`
`The New England Journal of Medicine
`Downloaded from nejm.org on September 28, 2015. For personal use only. No other uses without permission.
` Copyright © 2011 Massachusetts Medical Society. All rights reserved.
`
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`T h e ne w e ngl a nd jou r na l o f m e dicine
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`pation (26% and 31%), bone pain (25% and 28%),
`and arthralgia (27% and 23%). Most of these
`events were grade 1 or 2. Urinary tract infection
`was more frequent in the abiraterone acetate group
`(12%, vs. 7% in the placebo group; P = 0.02); these
`infections were also primarily grade 1 or 2 events.
`Adverse events resulting in treatment discontinu-
`ation occurred with similar frequency in the abi-
`raterone acetate and placebo groups (19% and
`23%, respectively; P = 0.09). The incidence of ad-
`verse events leading to dose modification or in-
`terruption was also similar in the two groups (Ta-
`ble 3 in the Supplementary Appendix).
`Adverse events associated with elevated min-
`eralocorticoid levels due to CYP17 blockade (fluid
`retention and edema, hypokalemia, and hyperten-
`sion), as well as cardiac disorders and liver-func-
`tion test abnormalities (Table 4), were deemed of
`special interest and were more common in the
`abiraterone acetate group than in the placebo
`group (55% vs. 43%, P<0.001). The incidence of
`fluid retention and edema was higher in the abi-
`raterone acetate group (31%, vs. 22% in the pla-
`cebo group; P = 0.04). Grade 1 or 2 peripheral
`edema accounted for most of these events. Hy-
`pokalemia also occurred in a higher proportion of
`patients in the abiraterone acetate group (17%,
`vs. 8% in the placebo group; P<0.001).
`Cardiac events (primarily grade 1 or 2) oc-
`curred at a higher rate in the abiraterone acetate
`group than in the placebo group (13% vs. 11%,
`P = 0.14), but the difference was not significant.
`The most frequently reported cardiac events were
`tachycardia (3% in the abiraterone acetate group
`and 2% in the placebo group, P = 0.22) and atrial
`fibrillation (2% and 1%, respectively; P = 0.29). All
`tachycardia events were grade 1 or 2; atrial fibril-
`lation events were grade 3 or lower. Despite the
`slightly higher incidence of cardiac events in the
`abiraterone acetate group than in the placebo
`group, there was no significant increase in fatal
`cardiac events in the abiraterone acetate group
`(1.1%, vs. 1.3% in the placebo group). No indi-
`vidual grade 4 adverse events occurred in 2% or
`more of patients in either treatment group.
`Abiraterone acetate treatment has been associ-
`ated with an elevation in aminotransferase levels. A
`grade 4 elevation in an aminotransferase level early
`in the study led to a protocol amendment specify-
`ing more frequent monitoring with liver-function
`tests during the first 12 weeks of treatment. Over-
`all, however, abnormalities in liver-function tests
`occurred at a similar frequency in the abiraterone
`
`Abiraterone
`acetate
`
`Placebo
`
`A Overall Survival
`100
`
`80
`
`60
`
`40
`
`20
`
`Survival(%)
`
`0
`
`0
`
`3
`
`6
`
`9
`12
`Months
`
`15
`
`18
`
`21
`
`00
`
`23
`
`736
`355
`
`657
`306
`
`520
`210
`
`282
`105
`
`68
`30
`
`Abiraterone
`acetate
`
`Placebo
`
`No. at Risk
`Abiraterone acetate
`Placebo
`
`797
`398
`
`B Time to PSA Progression
`100
`
`80
`
`60
`
`40
`
`20
`
`PSAProgression(%)
`
`0
`
`0
`
`3
`
`6
`
`9
`Months
`
`12
`
`15
`
`18
`
`00
`
`70
`
`490
`145
`
`292
`58
`
`139
`28
`
`59
`12
`
`Placebo
`
`Abiraterone
`acetate
`
`No. at Risk
`Abiraterone acetate
`Placebo
`
`797
`398
`
`C Progression-free Survival
`100
`
`80
`
`60
`
`40
`
`20
`
`Progression-freeSurvival(%)
`
`0
`
`0
`
`3
`
`6
`
`9
`Months
`
`12
`
`15
`
`18
`
`00
`
`490
`193
`
`352
`129
`
`202
`64
`
`76
`22
`
`14
`4
`
`No. at Risk
`Abiraterone acetate
`Placebo
`
`797
`398
`
`Figure 1. Kaplan–Meier Estimates of Overall Survival, Time to PSA Progres-
`sion, and Progression-free Survival According to Radiographic Evidence
`in the Intention-to-Treat Population.
`
`2000
`
`n engl j med 364;21 nejm.org may 26, 2011
`
`The New England Journal of Medicine
`Downloaded from nejm.org on September 28, 2015. For personal use only. No other uses without permission.
` Copyright © 2011 Massachusetts Medical Society. All rights reserved.
`
`ACTAVIS, AMNEAL, DR. REDDY’S LABORATORIES, SUN, TEVA, WEST-WARD-IPR2017-00853 - Ex. 1034, p. 6 of 11
`
`

`

`Abiraterone and Survival in Metastatic Prostate Cancer
`
`HazardRatioforDeath(95%CI)
`
`0.66 (0.56–0.79)
`
`0.64 (0.53–0.78)
`0.81 (0.53–1.24)
`
`0.64 (0.50–0.82)
`0.68 (0.53–0.85)
`
`0.63 (0.51–0.78)
`0.74 (0.55–0.99)
`
`0.59 (0.42–0.82)
`0.69 (0.56–0.84)
`
`0.66 (0.48–0.91)
`0.67 (0.55–0.82)
`0.52 (0.38–0.71)
`
`0.70 (0.52–0.94)
`0.62 (0.50–0.76)
`
`0.65 (0.52–0.81)
`0.69 (0.53–0.90)
`
`0.71 (0.58–0.88)
`0.64 (0.47–0.87)
`
`0.60 (0.48–0.74)
`0.73 (0.54–0.97)
`
`0.64 (0.51–0.80)
`0.69 (0.54–0.90)
`
`Subgroup
`
`All subjects
`Baseline ECOG performance status score
`0 or 1
`2
`Baseline BPI level
`<4
`≥4
`No. of previous chemotherapy regimens
`
`1 2
`
`Disease progression
`According to PSA concentration only
`According to radiographic findings
`Age
`<65 yr
`≥65 yr
`≥75 yr
`Visceral disease at entry
`Yes
`No
`Baseline PSA level above median
`Yes
`No
`Baseline lactic dehydrogenase level above median
`Yes
`No
`Baseline alkaline phosphatase level above median
`Yes
`No
`Geographic region
`North America
`Other
`
`OverallSurvival
`Abiraterone
`Placebo
`Acetate
`median (mo)
`14.8
`10.9
`
`15.3
`7.3
`
`16.2
`12.6
`
`15.4
`14.0
`
`—
`14.2
`
`14.4
`14.8
`14.9
`
`12.6
`15.4
`
`12.8
`16.2
`
`10.4
`—
`
`11.6
`—
`
`15.1
`14.8
`
`11.7
`7.0
`
`13.0
`8.9
`
`11.5
`10.3
`
`12.3
`10.4
`
`11.2
`10.7
`9.3
`
`8.4
`11.2
`
`8.8
`13.2
`
`8.0
`16.4
`
`8.1
`16.4
`
`10.7
`11.5
`
`0.50
`
`0.75
`
`1.00
`
`1.50
`
`AbirateroneAcetate
`Better
`
`Placebo
`Better
`
`Figure 2. Hazard Ratios for the Risk of Death, According to Subgroup.
`Hazard ratios are based on a nonstratified proportional-hazards model. The Eastern Cooperative Oncology Group
`(ECOG) grades the performance status of patients with respect to activities of daily living, with 0 indicating that the
`patient is fully active and able to carry on all predisease activities without restriction; 1 indicating that the patient is
`restricted in physically strenuous activity but is ambulatory and able to carry out work of a light or sedentary nature,
`such as light housework or office work; and 2 indicating that the patient is ambulatory and up and about more than
`50% of waking hours and is capable of all self-care but unable to carry out any work activities. Dashes indicate that
`the median time to death had not been reached for the indicated patient subgroup. The size of the circles is propor-
`tional to the size of the subgroup. BPI denotes Brief Pain Inventory–Short Form, CI confidence interval, and PSA
`prostate-specific antigen.
`
`acetate and placebo groups, including changes of
`any grade in liver-function tests (10% and 8%, re-
`spectively), grade 3 or 4 changes in liver-function
`tests (3.5% and 3.0%), grade 3 or 4 elevations in
`aspartate aminotransferase levels (1.4% and 1.6%),
`grade 3 or 4 elevations in alanine aminotransfer-
`ase levels (1.0% and 1.1%), and grade 4 eleva-
`tions in aminotransferase levels (0.3% and 0.5%).
`
`A total of 11% of patients in the abiraterone
`acetate group and 13% of patients in the placebo
`group died within 30 days after the last dose of
`study medication, primarily as a result of disease
`progression. A lower proportion of patients in the
`abiraterone acetate group than in the placebo
`group had an adverse event that resulted in death
`(12% vs. 15%).
`
`n engl j med 364;21 nejm.org may 26, 2011
`
`2001
`
`The New England Journal of Medicine
`Downloaded from nejm.org on September 28, 2015. For personal use only. No other uses without permission.
` Copyright © 2011 Massachusetts Medical Society. All rights reserved.
`
`ACTAVIS, AMNEAL, DR. REDDY’S LABORATORIES, SUN, TEVA, WEST-WARD-IPR2017-00853 - Ex. 1034, p. 7 of 11
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Table 2. Results of Multivariate Analysis of Overall Survival in the Intention-to-Treat Population.*
`
`Variable
`
`Treatment: abiraterone acetate vs. placebo
`
`ECOG score: 0 or 1 vs. 2
`
`Pain: absent vs. present
`
`Previous chemotherapy regimens: 1 vs. 2
`
`Evidence of progression: PSA concentration only vs.
`radiographic findings
`
`Model Fit
`
`Coefficient
`
`−0.4±0.09
`
`−0.9±0.12
`
`−0.4±0.09
`
`−0.2±0.09
`
`−0.3±0.10
`
`P Value
`
`<0.001
`
`<0.001
`
`<0.001
`
`0.006
`
`0.01
`
`Hazard Ratio
`for Death
`(95% CI)
`
`0.66 (0.55–0.78)
`
`0.40 (0.32–0.50)
`
`0.67 (0.56–0.79)
`
`0.78 (0.66–0.93)
`
`0.78 (0.64–0.94)
`
`* Data on patients who had not died by the time of analysis were censored on the last dat