`
`
`
`ESTABLISHED IN 1812
`
`MAY 26, 2011
`
`VOL. 364 NO. 21
`
`Abiraterone and Increased Survival in Metastatic Prostate Cancer
`.l
`1!
`Wrens. iv;
`beret}.
`
`inwar'
`
`ABSTRACT
`
`QACKQRCEUNS
`
`Biosynthesis of extragonadal androgen may contribute to the progression ofcas—
`nation—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.
`
`fiKYRQDS
`
`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 able
`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.
`
`RELSQLYS
`
`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.
`
`CEBNCLQSEONS
`
`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
`Clinical’l‘rialsgov number, NC’l‘00638690.)
`
`NENGLJ MED364;ZI
`
`rum/Lorre MAY26,2011
`
`From the institute of Cancer Research and
`Royal Marsden Hospital, Sutton 0.5.8.,
`A.Z., D.B.),
`Institute of Cancer Sciences,
`Glasgow (RJJ), Cardiff University, Velindre
`Hospital, Cardiff (J,N.S.), and Cambridge
`(HP) ——all in the United Kingdom; MD. An-
`derson Cancer Center, Houston (CJrL., E.E.);
`Ortho Biotech Oncology Research and Devel-
`opment (a unit ofCougar Biotechnology), Los
`Angeles (A.M., N.C., T.K., C.M.H.); lnstitut
`Gustave Roussy, Villejuif(K.F., Y.i..). and Cen-
`tre Leon Bérard, Lyon (A.F.) «both in France;
`Cross Cancerinstitute, Edmonton,AB (SN),
`BC CancerAgency,VancouverCancerCentre,
`Vancouver (K.N.C.), University of Calgary,
`Calgary, AB (TC), and BC Cancer Agency,
`Centre for the Southern Interior, Kelowna
`(SLE) —all in Canada; Oncology Hematol-
`ogy Consultants, Sarasota, FL (LC); Nevada
`Cancer Institute, Las Vegas (0.8.6,); Univer~
`sityofMontreal. Montreal (RS); Haematol-
`ogy and Oncology Clinics of Australasia,
`Milton, Australia (PM); UCL Cancer insti-
`tute, London (S.H.); University of Colorado
`Cancer Center, Aurora (TWP); Texas Oncol-
`ogy-Baylor Charles A, Sammons CancerCen-
`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 (CJ.R.); San Camille and Forlanini
`Hospitals, Rome (CNS); 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 (HJS). Address reprint re»
`quests to Dr. de Bono at the Institute of
`Cancer Research and Royal Marsden Hospi-
`tal, Downs Rd. Sutton, Surrey SM2 SPT, Unit-
`ed Kingdom. or atjohann.de-bono@icriac.ul<i
`*Additional COU-AA—301 investigators are
`listed in the Supplementary Appendix,
`available at NEjMorg,
`N Englj Med 2011;364:19952003
`Copyright © 2011 Massachusetts Medical Society.
`1995
`
`The New England Journal of Medicine
`Downloaded from nejmorg on September 28, 2015. For personal use only. No other uses without permission.
`Copyright © 201 1 Massachusetts Medical Society, All rights reserved.
`
`JANSSEN EXHIBIT 2159
`
`Wockhardt v. Janssen |PR2016-01582
`
`JANSSEN EXHIBIT 2159
`Wockhardt v. Janssen IPR2016-01582
`
`

`

`Mr N €31 W ii 5 7 {3 LA N i} if) E} 31 N A i. of M £7.13“? 1 N ii
`
`" “@011 THE PAST 70 YEARS, DEPLETING OR
`
`. blocking the action of androgens has been
`JJJJa.
`the standard of care for men with advanced
`
`prostate cancer.1 Androgen deprivation results in a
`decrease in the concentration ofprostate—specific
`antigen (PSA) as well as tumor regression and re—
`liefofsymptoms 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 androgenvreceptor
`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: docetaxel“ as first~line and cabazitaxelS as
`
`second—line cytotoxic chemotherapy, and active cel-
`lular immunotherapy with sipuleucel—T.‘S
`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.” 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.”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.”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 Groupnv22 (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 (ECOGW per-
`formance status score of 2 or less (on a scale from
`
`0 to S, 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
`
`22.5 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) MED364;21
`
`NE}M.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 © 201 1 Massachusetts Medical Society. All rights reserved.
`
`

`

`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)?“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
`placebd 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
`250% in the PSA concentration from the pretreat-
`ment baseline PSA value, which was confirmed
`after 24 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 5.50%], pro-
`gressive disease would be considered to have
`occurred when the PSA level increased 25% over
`
`the increase was a
`the nadir, provided that
`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 22.0 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 ofeach 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 ofeach 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 NEJMbrg.
`
`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 ofadverse events and serious ad~
`verse events, including adverse events detected by
`
`N ENGL} MED 364m
`
`NE}M.ORG MAY 26, 2011
`
`1997
`
`The New England Journal of Medicine
`Downloaded from nejmorg on September 28, 2015. For personal use only. No other uses without permission.
`Copyright © 20l l Massachusetts Medical Society. All rights reserved.
`
`

`

`iiés‘ 3: iii )3!
`
`if. N {3: E. 23. N i) 3
`
`01.} R, N ,:
`
`’_. a; M iii DE (1 i N i
`
`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-
`naire”; the score for fatigue, as evaluated by
`means of the Brief Fatigue Inventory instrument”;
`information on medical resource utilization”; and
`
`counts of circulating tumor cells.30
`
`STU DY 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 ofthe
`data, analyses ofthe 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
`of0.80 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) of0.05, 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% of797 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.
`
`
`RESULTS
`
`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 ofdis—
`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} MED 364:21
`
`NE}M.ORG MAY 26, 2011
`
`The New England Journal of Medicine
`Downloaded from nejmorg on September 28, 2015. For personal use only. No other uses without permission.
`Copyright © 201 1 Massachusetts Medical Society. All rights reserved.
`
`

`

`ABIRATERONE AND SURVIVAL IN METASTATIC PROSTATE CANCER
`
`
`
`i i l i
`
`Age
`
`Median (range) — yr
`
`>75 yr—vno. ofpatients/totai no (%)
`Disease location — no of patients/total no. (%)
`Bone
`Node
`Liver
`
`BPiSF score for paint
`No of patients
`Median score (range)
`No ofprevious cytotoxic chemotherapyregimens -
`no of patients/total no (%)
`
`l 2
`
`ECOG performance status — no. onatients/total no. (%)
`0 or 1
`2
`
`Prostate-specific antigen
`No ofpatients
`
`788
`
`393
`
`Median((range) ~— rig/mi
`
`3“ See Table 2In the Supplementary Appendix for more baseline demographic and clinical characteristics.
`1‘ The Brief Pain inventory-Short Form (BPLSF) rates pain on a scale oiO 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.
`
`128.8 (GA—9253.0)
`
`137.7 (O.6-10114.0)
`
`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.0rg).
`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 ofradiographic 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} MED 364m
`
`NEJMORG MAY 26,2011
`
`1999
`
`The New England Journal of Medicine
`Downloaded from nejmorg on September 28, 2015. For personal use only. No other uses without permission.
`Copyright © 201 1 Massachusetts Medical Society. All rights reserved.
`
`
`Teeter 3. BaselineDemOgraphic and Clinical Characteristics ofthe Patients.*
`Abiraterone Acetate
`(N = 797)
`
`Characteristic
`
`
`
`Placebo
`(N = 398)
`
`69 (39—90)
`
`111/397 {28)
`
`
`
`357,139? (90)
`164/397 (41)
`30/397 (8)
`
`_
`
`394
`
`3.0 (0—10)
`
`275/398 (69)
`123/398 (31)
`
`353/398 (89)
`45/398 (11)
`
`69 (42-95)
`
`220/797 (28)
`
`709/797 (89)
`361/797 (45)
`90/79? (11)
`
`792
`
`3.0 (0—10)
`
`558/797 (70)
`239/792 (30)
`
`715/797 (90)
`82/797 (10)
`
`

`

`0 {1 R N A it
`
`:71 M E}: 1'} i C i N 1.
`
`1F 1‘ N E51 W i“: N t}: L A N i)
`
`i
`
`ii, A Overall Survival
`100
`
`2*:
`E
`E
`i?)
`
`60
`
`40
`20
`
`0
`
`80
`
`
`Abiraterone
`g acetate
`‘
`1.x..‘fig:
`""""""
`
`
`r' -—-1—'
`l
`12
`15
`18
`21
`Months
`
`6
`
`9
`
`0
`
`3
`
`No. at Risk
`Abiraterone acetate 797
`Placebo
`398
`
`736
`355
`
`657
`306
`
`520
`210
`
`282
`105
`
`68
`30
`
`2
`3
`
`0
`0
`
`B Time to PSA Progression
`100
`
`
`
`
`Abiraterone
`acetate
`‘L......__.,...._.-.
`
`”
`
`________
`
`Placebo
`
`
`”r
`I
`t
`1
`9
`12
`15
`18
`Months
`
`No. at Risk
`Abiraterone acetate 797
`Placebo
`398
`
`490
`145
`
`292
`$8
`
`139
`28
`
`S9
`12
`
`7
`o
`
`0
`o
`
`C Progression-free Survival
`100
`
`A 80
`2\°’C
`
`a 60
`8
`'50
`Q-
`e
`2,
`
`40
`
`20
`
`0
`
`
`
`
`
`Progression-freeSurvival(%)
`
`00O
`
`5‘)O
`
`4:.O
`
`NO
`
`0
`
`
`
`
`
`i iil
`
`i
`
`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, P2022) and atrial
`fibrillation (2% and 1%, respectively; P=O.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
`
`i
`i
`i
`E
`g
`
`i
`:
`1i
`i
`i
`l
`
`
`
`
`
`”'Tf
`12
`
`v
`15
`
`1
`9
`Months
`
`Abiraterone
`acetate
`
`‘1
`18
`
`0
`0
`
`No. at Risk
`i Abiraterone acetate 797
`i
`Placebo
`398
`
`490
`193
`
`352
`129
`
`202
`64
`
`76
`22
`
`14
`4
`
`
`
`Sigma 1,. Kaplan—Meier Estimates ofOverall Survival, Time to PSA Progres‘
`g sion, and Progression-free SurvivalAccerding to Radiographic Evidence
`i
`in the lntention~touTreat PopUlafion.
`,
`
`
`
`
`i
`
`2000
`
`N ENGL} MED 364m
`
`NE}M.ORG MAY 26, 2011
`
`The New England Journal of Medicine
`Downloaded from nejmcrg on September 28. 2015. For personal use only. No other uses without permission.
`Copyright © 201 l Massachusetts Medical Society. All rights reserved.
`
`

`

`ABIRATERONE AND SURVIVAL IN METASTATIC PROSTATE CANCER
`
`
`
`Overall Survival
`Abiraterone
`Acetate
`
`Placebo
`
`Hazard Ratio for Death (95% Cl)
`
`Subgroup
`
`I i
`
`I
`g
`
`Allsubiccts
`Baseline ECOG performance status score
`00:1 _
`,
`‘
`2
`Baseline 8131 level
`<4
`_
`_
`24
`No. of previous chemotherapy regimens
`1
`2
`Disease progression
`According to PSA concentration only
`According f0 radiographic findings
`Age
`<65 yr
`265 yr
`‘
`-
`275):
`-
`Visceral disease at entry
`Yes -
`No
`Baseline PSA level above median:
`Yes
`‘
`-
`-
`‘
`No
`Baseline lactic dehydrogenase level above median
`Yes
`_
`‘
`‘-
`,
`No
`Baseline alkaline phosphatase leIIEI above median
`Yes
`- No
`Geographic region
`North Amencaf
`Other
`
`-
`
`.
`
`_-
`
`I
`
`_
`
`i
`
`_
`
`-
`
`.
`
`.
`
`-
`
`.
`
`,
`
`.
`
`_
`
`'
`
`_-
`L
`
`l
`
`*
`
`l
`
`‘
`
`g
`
`14.4
`14.8
`1.4.0
`
`- 112
`10. 7
`' 9.1
`
`‘
`
`- (—————¢-—-—-—i
`i—-O—-l
`I—-—-—o—~—_—_-{
`‘-
`
`12.6.
`154
`12.8
`16.2
`
`10.4
`_
`.
`11.6
`~
`
`15.1
`14.8
`
`.
`
`_
`
`8.0 _
`16.4
`8.1
`__ 16.4 ‘
`
`_
`
`_
`
`10.7
`11.5
`
`l
`I
`
`Il
`
`l
`I
`l
`l
`;
`g
`I
`E
`E
`l
`l
`l
`
`]
`l
`
`l
`l
`l
`
`
`
`median (mo)
`14.8: -
`‘
`10.9
`
`Iw-O—s—l
`
`I
`
`115.3
`7.3
`16.2
`.126 '
`
`15.4
`14.0
`
`—
`14.2
`
`11.7
`7.0
`13.0
`8.9
`
`11.5
`10.3
`
`12.3
`10.4
`
`3
`I
`i
`t———¢-—-—%
`i——-————-o—.b———i
`-
`l
`E
`t—-—O—-—l
`;
`I~—~—o————I
`:
`:
`:
`I-———~o—-—i
`I——o———{
`I
`I
`2
`l———-—-O—-l
`E
`‘
`lm-C-e—I
`:
`:
`:
`
`-
`
`0.68 (0564.79)
`
`‘
`
`0.64 (0.53-0.78)
`0.81 (0.53-124)
`0.64 (0.50-0.82)
`0.68 (0.534185)
`
`0.63 (0.514118)
`0.74 (0.55-099)
`.
`0.59 (0.42-0.82)
`0.69 (0.56—0.84)
`_
`0.66 (0.48.031)
`0.67 (0.55—0.82)
`0.52 (0.38431)
`
`l
`
`0.70 {0.524.941
`0.62 (0.50-0.76)
`‘
`L
`0.65 (0.52—0.81)
`”0.69 (0.53—0.90)
`
`I
`
`'
`
`0.?1(0,58—0.88) -~,
`0.64 (0.47—0.87)
`1
`_
`-
`0.60 (048.074)
`073(054409?)
`
`.
`
`4,
`
`l
`E
`l
`3
`5
`l
`i
`g
`E
`g
`i
`g
`E
`g
`1
`g
`3
`E
`;
`d
`é
`l
`l
`8.4 W i
`l
`:
`11.2
`I—O——l
`g
`I
`E '
`I
`8.8
`I———-o—-——-|
`:
`l
`13.2
`' Wu) ’
`l
`l
`1
`3
`I—-~o—-~—(
`i
`l
`;
`I—————o——-——-|
`l
`.
`E
`_
`*
`3
`l
`;
`I———-—o——-I
`g
`I
`(«e—W: ‘
`5
`l
`:
`l
`064(0514080) l
`:
`(«wow-mt
`;
`r-mrm‘fu'l
`§
`I-—-——o-———I
`-
`0.69 (0.54-0.90)
`i
`«Mu—p
`l
`0.50
`0.75
`1.00
`1.50
`I
`l
`Abiraterone Acetate Placebo
`Better
`Better
`I
`I
`
`figum2 HazardRatiosfor the Risk ofDeath According to Subgroup
`
`Hazard ratios are based on a nonstratlfied proportional-hazards model The Eastern Cooperative Oncology Group
`
`
`(E1206) grades the petformance status of patients with respect to activities of: daily living, with 0 indicating that the ‘
`
`EEg
`patient is fully active and able to carry on all predisease activities without restriction; lIndicating that the patIént Is
`restrictedIn physically strenuous activity butIs ambulatory and able to carry out work ofa light or sedentary nature, .
`
`such aslight housowork or office work; and 2 indicatmg that the patientIs ambulatory and up and about morethan ,
`
`50% olwaking 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 notbeen reached for the indIcated patient subgroup The size of the circlesIs propor»
`
`tional to the size ofthe subgroup BPl denotes Brief Pam inventorwshort Form, Ci confidence interval and PSA
`'
`
`
`
`prostatespecific antigen
`
`EE lEIE
`
`A total of 11% of patients in the abiraterone
`acetate and placebo groups, including changes of
`any grade in liver‘function tests (10% and 8%, re— acetate group and 13% ofpatients in the placebo
`spectively), grade 3 or 4 changes in liver-function group died within 30 days after the last dose of
`tests (3.5% and 3.0%), grade 3 or 4 elevations in
`study medication, primarily as a result of disease
`progression. A lower proportion of patients in the
`aspartate aminotransfcrase levels (1.4% and 1.6%),
`abiraterone acetate group than in the placebo
`grade 3 or 4 elevations in alanine aminotransfer—
`group had an adverse event that resulted in death
`2156 levels (1.0% and 1.1%), and grade 4 eleva-
`(12% VS. 15%).
`tions in aminotransferase levels (0.3% and 0.5%).
`
`N ENGL} MED 364;21
`
`NE}M.ORG MAY 26, 2011
`
`2001
`
`The New England Journal of Medicine
`Downloaded from nejmorg on September 28, 2015. For personal use only. No other uses without permission.
`Copyright © 201 1 Massachusetts Medical Society. All rights reserved.
`
`

`

`flit
`
`b} li EV ii N G l, A N l} j {:3 U R N A l. or“ M E l) i C} N if.
`
`
`: “table 2. Results of Multivariate Analysis ofOverall Survival in [the intention-tmtrean, Populatienfi
`
`Variable
`
`
`Treatment: abiraterone acetate vs. placebo
`i ECOG score: 0 or 1 vs. 2
`' Pain: absent vs. present
`Previous chemotherapy regimens: 1 vs. 2
`
`Model Fit
`
`Coefficient
`~0.4¢0.09‘
`—0.9:0.12
`peace
`—0.2:0.09
`
`_
`
`PValue
`<0.0010
`<0.001
`_ (0.001
`0.006
`
`41310.10 -
`
`‘ 0.01
`
`
`Hazard Ratio
`for Death
`E
`l
`(95% Cl)
`l
`{
`
`0.66 (0.55438)
`0.40 (0.32~0.50)
`0.57 (0564.79)
`0.78 (0.66-0.93)
`
`0.?8 (0.64-0.94)
`
`l
`
`Evidence of progression: PSA concentration only vs.
`radiographic findings
`l
`-
`‘5 Data on patients who had not died by the time ofanalysis were censored on the last date the patient was known to be
`alive or was available For Follow-up. Each test was carried out at a significance level oi0.05. Cl denotes confidence inter«
`val, ECOG Eastern Cooperative Oncology Group, and PSA prostate—specific antigen.
`
`
`DISCUSSION
`
`In this phase 3 study of abiraterone acetate, an
`inhibitor of androgen biosynthesis, surviVal was
`prolonged among patients with metastatic castra—
`tion—resistant prostate cancer who had received
`chemotherapy. Increased survival was observed
`in all patient subgroups and the superiority of the
`treatment group was shown across all prespecified
`secondary end points. The use of hormonal agents
`is typically not considered in patients who have
`received chemotherapy. These results show that
`continued androgen—receptor signaling contrib—
`utes to disease progression, and they provide
`support for the evaluation of other endocrine
`therapies in