I Articles
`
`~ +~ ~ Abiraterone acetate plus prednisone versus placebo plus
`prednisone in chemotherapy-naive men with metastatic
`castration-resistant prostate cancer (COU-AA-302):
`final overall survival analysis of a randomised, double-blind,
`placebo-controlled phase 3 study
`
`Charles) Ryan, Matthew R Smith, Karim Fizazi, Fred Saad, Peter FA Mulders, Cora N Sternberg, Kurt Miller, Christopher J Logothetis, Neal D Shore,
`Eric J Small, Joan Carles, Thomas W Flaig. Mary-Ellen Taplin, Celestia S Higano, Paul de Souza, JohannS de Bono, Thomas W Griffin, Peter De Porre,
`Margaret K Yu, Youn C Park,jinhui U, Thian Kheoh, Vahid Naini, Arturo Molina, Dana E Rothkopf. for the COU-AA-302 Investigators*
`
`Summary
`Background Abiraterone acetate plus prednisone significantly improved radiographic progression-free survival
`compared with placebo plus prednisone in men with chemotherapy-naive castration-resistant prostate cancer at the
`interim analyses of the COU-AA-302 trial Here, we present the prespecified final analysis of the trial, assessing the
`effect of abiraterone acetate plus prednisone on overall survival, time to opiate use, and use of other subsequent
`therapies.
`
`Methods In this placebo<011troUed, double-blind, randomised phase 3 study, 1088 asymptomatic or mildly
`symptomatic patients with chemotherapy-naive prostate cancer stratified by Eastern Cooperative Oncology
`performance status (0 -vs 1) were randomly assigned with a permuted block allocation scheme via a web response
`system in a 1:1 ratio to receive either abiraterone acetate (1000 mg once daily) plus prednisone (5 mg twice daily;
`abiraterone acetate group) or placebo plus prednisone (placebo group). Coprimary endpoints were radiographic
`progression-free survival and overall survival analysed in the intention-to-treat population. The study is registered
`with ClinicalTrials.gov, number NCI00887198.
`
`Findings At a median follow-up of -4-9·2 months (IQR -4-7·0-51·8), '741 (96%) of the prespecified 773 death events for
`the final analysis had been observed: 35-4- (65%) of 546 patients in the abiraterone acetate group and 387 ('71%) of
`5-4-2 in the placebo group. 238 (44%) patients initially receiving prednisone alone subsequently received abiraterone
`acetate plus prednisone as aossover per protocol (93 patients) or as subsequent therapy (1-4-5 patients). Overall,
`365 (6'7%) patients in the abiraterone acetate group and -4-35 (80%) in the placebo group received subsequent treatment
`with one or more approved agents. Median overall survival was significantly longer in the abiraterone acetate group
`than in the placebo group (34 ·7 months [95% CI 32 · '7-36 · 8)-vs 30 · 3 months [28 ·7-33 · 3); hazard ratio 0 · 81 [95% CI
`0 · '70-0 · 93]; p=O · 0033). The most common grade 3-4 adverse events of special interest were cardiac disorders (41 [8%]
`of 542 patients in the abiraterone acetate group vs 20 [4%] of540 patients in the placebo group), increased alanine
`aminotransferase (32 [6%]-vs four [<1%)), and hypertension (25 [5%]-vs 1'7 [3%)).
`
`Interpretation In this randomised phase 3 trial with a median follow-up of more than 4 yean, treatment with
`abiraterone acetate prolonged overall survival compared with prednisone alone by a margin that was both clinically
`and statistically significant. These results further support the favourable safety profile of abiraterone acetate in
`patients with chemotherapy-naive metastatic castration-resistant prostate cancer.
`
`Funding Janssen Research & Development.
`
`I ntrocluction
`An overarching feature of the recent management of
`metastatic castration-resistant prostate cancer is the use
`of sequential therapies. Before 2010, the only approved
`systemic treatment associated with improved overall
`sUTVival was docetaxel.U Over the past 4 years, five
`therapeutics with demonstrated survival benefit in
`randomised clinical studies have become available, and
`are commonly used in sequence. J-n Given the chronicity
`and heterogeneity of metastatic castration-resistant
`
`prostate cancer, administration of such subsequent
`therapies may confound the measurement of the effect
`of a particular treatment on overall survival.
`Abiraterone acetate is a prodrug of abiraterone, an
`orally available inhibitor of the cytochrome P450 c17
`enzyme complex critical to androgen production. Oral
`abiraterone acetate plus prednisone demonstrated a
`significant improvement in survival, compared with
`placebo plus prednisone, for patients with metastatic
`castration-resistant prostate cancer with progression of
`
`www.thelancet.com/oncology Vol16 February 2015
`
`l1111Cft0ncol2015; 16: 152-60
`Published Onn,.
`January 16, 2015
`http:/ldx.dol.org/10.10161
`51470-2045(14)71205-7
`See Comment page 119
`•Additional inve5tigators listed
`In the appendix
`Helen Dlller Family
`Comprehensive cancer Center,
`University of california
`San Fnndsco. San FranclscD,
`CA. USA (ProfCJ Ryan MD,
`Prof E) Small MD); Harvard
`Medical School and
`M.....:husettsGeneral
`Hospibll, Boston, MA, USA
`(Prof M RSmith MD); lnstitut
`liustave Roussy, University
`of Paris Sud, Vlllejuif, France
`(Prof K Flzazl MD); University of
`Montr4a~ MontrNI, Qu6bec,
`Canada (Prof F 5aad MD);
`RadboudUniverslty Medical
`Centre. Nijmegen, Netherlancb
`(Prof P FA Mulders MD);
`San Camillo and Forlanini
`Hospibls, Rome, Italy
`(C N Sternberg MD); Charite
`Berlin, Berlin, Germany
`(Prof K Miller MD); MD
`Anderson cancer Center,
`HoustDn, TX. USA
`(ProfCJ L.ogothetis MD);
`c.rolina Urologic lleseard1
`Center, Atlantic Urology Clinics,
`Myrtle Beach, SC, USA
`(N D Shor~~ MD); Vall d'Hebron
`University Hospital and Vall
`d'Hebron Institute of
`Oncology, Barulona. Spain
`(J Carles MD); University of
`Colorado Cancer Center and
`University of Colorado School
`of Medicine, Aurora, CO, USA
`(TW Flaig MD); Dana-Farber
`cancer Institute, Harvard
`Medical Schoo~ Boston, MA,
`USA (M-E Taplin MD);
`University of washington, Fred
`Hutchinson Cancer Research
`
`152
`
`JANSSEN EXHIBIT 2071
`Mylan v. Janssen IPR2016-01332
`
`

`

`Articles I
`
`Center, Seattle, WA, USA
`(ProfC S Higano MD); Uniwnity
`of-rn Sydney Sd>oolof
`Medicine and Ingham
`Institute, Uverpoo~ Aust,..la
`(Prof P de Sotna MB); The
`lnstltuteofCincerResearch
`and the Royal Marsden
`Haspito~ Sutton, United
`Kingdom
`(Profj Sde Bono MB ChB);
`Janssen-..d!a
`Devoi!lopment, LosAngoles, CA,
`USA (TW Griffin MD, M KYu MD,
`T Kheoh PhD, V Naini PharmD);
`Janssen Research a
`Development, Beerse, Belgium
`(P De Porre MD); Janssen
`Resurch a Development,
`Raritan, NJ, USA Cf C Park PhD,
`JLiPhD),JanssenReoard!a
`Devoolopment, Menlo Park, CA,
`USA (A Molina MD); and
`Memorial Sloan Kettering
`cancer Center, New York, NY,
`USA (D E Raltlkopf MD)
`
`Correspondence to:
`Prof Charles J Ryan,
`Genitourinary Medical Oncology
`Program, UCSF Helen Diller
`Family Comprehensive cancer
`CentEr, 16o0 Divisadero Stn!et,
`San Francisco, CA. 94115, USA
`l)'lllnc(!lmedicine.ucsf.odu
`
`See Onfine for appendix
`
`placebo plus prednisone group and in long-term follow(cid:173)
`up, investigator assessment that abiraterone acetate
`therapy would be safe and beneficial, not currently
`receiving prostate cancer therapy other than luteinising
`hormone-releasing hormone analogues, no concomitant
`administration of cytotoxic chemotherapy, and ECOG
`performance status ofO, 1, or 2.
`
`Procedures
`Patients in the abiraterone acetate group received
`abiraterone acetate (Patheon, Mississauga, Canada) at a
`dose of1000 rng (aclrnilllstered as four 250 rng tablets) and
`prednisone at a dose of 5 rng orally twice daily, while those
`in the placebo group received four placebo tablets once
`daily with the same dose of prednisone as in the
`experimental group. The planned duration for study
`treatment was until radiographic progression of disease,
`clinical progression, or both, or if the patient had
`unresolved adverse events, initiated new anticancer
`treatment, was lost to follow-up, or withdrew informed
`consent for treatment. Overall survival follow-up was for
`60 months or until the patient died, was lost to follow-up,
`or withdrew consent for the study follow-up. Patients were
`allowed only two dose reductions for abiraterone acetate,
`the first to three tablets (750 mg) daily and, if indicated, a
`second to two tablets (500 rng) daily. The most common
`triggers for dose reduction were to restart dosing (referring
`to restarting of dosing after a patient had an adverse event;
`31 [6%] patients in the abiraterone acetate group and
`eight (2%] patients in the placebo group) and adverse
`events or toxicity (six [1%] patients in the abiraterone
`acetate group and one [<1%] in the placebo group).
`Radiographic assessments with CT or MRI and bone
`scanning were done every 8 weeks during the first
`24 weeks and every 12 weeks thereafter. Clinical safety
`assessments included laboratory monitoring of blood
`chemical levels, haematological values, coagulation
`studies, serum lipids, kidney function, and PSA at
`baseline and prespeci:fied visits.
`
`Outcomes
`The coprimary endpoints were radiographic progression(cid:173)
`free survival and overall survival. Overall survival has
`been reported previously in interim analyses,.,,. and the
`analysis of radiographic progression-free survival
`requiring 378 events was fully matured as reported
`previously.' The focus of this report is an update of overall
`survival from the final analysis and the secondary
`endpoint of time to opiate use for cancer-related pain.
`Long-term safety data are also reported.
`
`Statistical analysis
`A final analysis was planned when 773 death events had
`occurred. The group-sequential design was used for the
`overall survival endpoint with O'Brien-Fleming boundaries
`as implemented by the Lan-DeMets alpha spending
`method. Median follow-up was estimated with the
`
`disease after administration of chemotherapy."" In
`chemotherapy-naive patients, abiraterone acetate plus
`prednisone delayed radiographic progression, prevented
`the onset of symptoms, and preserved quality of life,
`compared with placebo plus prednisone.'·10
`1 However, at
`the interim analyses, overall survival results did not cross
`the prespecified efficacy boundary for statistical
`significance as defined by O'Brien and Fleming."
`Here, we present the final overall survival analysis of
`the COU-AA-302 trial of abiraterone acetate plus
`prednisone versus placebo plus prednisone
`in
`chemotherapy-naive patients with metastatic castration(cid:173)
`resistant prostate cancer.
`
`•1
`
`Methods
`Study design and participants
`The patient population for this multinational, double(cid:173)
`blind, randomised, placebo-controlled phase 3 trial has
`been described previously.'·10 Briefly, patients aged 18 years
`or over with histologically or cytologically confirmed
`adenocarcinoma of the prostate, prostate-specific antigen
`(PSA) progression according to Prostate Cancer Clinical
`Trials Working Group 2 (PCWG2) criteria, or radiographic
`progression in soft tissue or bone with or without PSA
`progression, ongoing androgen deprivation therapy with
`a serum testosterone level of less than 50 ngjdL
`(1·7 nmoljL), an Eastern Cooperative Oncology Group
`(ECOG) performance status grade of 0 or 1, with Brief(cid:173)
`Pain Inventory-Short Form scores of0--1 (asymptomatic)
`or 2-3 (mildly symptomatic), previous anti-androgen
`therapy followed by documented PSA progression after
`discontinuing the anti-androgen, and haernatological and
`chemical laboratory values that met predefined criteria
`were eligible. Patients with visceral metastases or
`patients who had received previous
`therapy with
`ketoconazole for more than 7 days were excluded. The
`review boards at all participating institutions approved
`the study, conducted according to the principles of the
`Declaration of Helsinki and the Good Clinical Practice
`guidelines of the International Conference on Harmoni(cid:173)
`sation. All patients provided written informed consent to
`participate in the study.
`
`Randomisation and masking
`Patients were randomly assigned with a permuted block
`allocation scheme in a 1:1 ratio to receive either abiraterone
`acetate and prednisone (abiraterone acetate group), or
`placebo plus prednisone (placebo group). Patients were
`stratified according to baseline ECOG performance
`status (0 vs 1). After review of the second interim analysis
`results, the independent data monitoring committee
`recommended unblinding of the study and crossover of
`patients in the placebo group to receive abiraterone acetate
`plus prednisone. Eligibility criteria for patients receiving
`placebo plus prednisone who crossed over to abiraterone
`acetate and prednisone were instituted for ethical reasons.
`They included previous participation in the COU-AA-302
`
`www.thelancet.mm/orKOiogy Vol16 FebrLNLry 2015
`
`153
`
`

`

`I Articles
`
`Kaplan-Meier method, where patients were censored at
`death. The primary statistical method of comparison for
`the time-to-event endpoints was the stratified log-rank
`test stratified by baseline ECOG score. The Cox
`proportional-hazards model was used to estimate the
`hazard ratio (HR) and its associated CI. A planned
`sensitivity analysis to adjust for crossover effect via the
`iterative parameter estimate (IPE) method" was done to
`estimate the true treatment effect under an accelerated
`failure time model. The IPE method retains all patients
`in the treatment groups to which they were originally
`randomised. By conditioning on having observed patient
`switch times, the IPE method iteratively estimates the
`treatment effect by discounting the survival times of
`crossover patients so that they are comparable to the
`survival times of non-crossover patients, assuming the
`experimental group
`is always
`receiving effective
`treatment while the control group is receiving the same
`effective treatment at the start of crossover or subsequent
`therapy. An exploratory multivariate analysis for overall
`survival evaluated the potential effect of important
`prognostic factors on the treatment effect. Based on
`multivariate analysis at the second interim analysis, the
`following significant (univariate, p<O · 01) prognostic
`factors were included in the Cox regression model: ECOG
`performance status score, baseline serum PSA, baseline
`lactate dehydrogenase, baseline alkaline phosphatase,
`
`baseline haemoglobin, bone metastasis at baseline, and
`age. Efficacy analyses compared
`the
`randomised
`abiraterone acetate and placebo treatment groups. Data
`for exposure and safety analyses are reported by
`treatment received (ie, for patients assigned to the
`abiraterone acetate group who received abiraterone
`acetate plus prednisone, and patients assigned to the
`placebo group who received placebo plus prednisone);
`for patients assigned to the placebo group who later
`crossed over to abiraterone acetate, safety data from
`before crossover were used.
`We used SAS version 9.1 for all key analyses.
`The study is registered with ClinicalTrials.gov, number
`NCf00887198.
`
`Role of the funding source
`Employees of the funder participated in the development
`of the trial design, data monitoring, data collection, data
`analysis. data interpretation, and writing of the manuscript.
`The first manuscript draft was initially written by the lead
`academic author (CJR) with sponsor input and editorial
`assistance funding. All coauthors subsequently provided
`input and approval to submit for publication. The authors
`assume responsibility for the completeness and integrity
`of the data, the study fidelity to the protocol, and statistical
`analysis. CJR had full access to all of the data and the final
`responsibility to submit for publication.
`
`11533 patient$ ~ssed for eligibility
`H 445 Ineligible at screening
`
`I
`
`I
`
`11088 ranclomlsed
`
`I
`
`•
`
`542 assigned to placebo plus prednisone
`542 in ITT population
`2 did not receive study drugs
`86ongoing
`454 discontinued
`351 due to progre55M! disease
`540 In safety population
`
`:---------------------------------------------------------------------------------1
`
`86 in the placebo group
`58 ongoing
`28 discontinued
`18 due to progre .. ive disease
`
`1
`
`7 in plac.ebo group
`7 dlsmntlnued
`1 due to progressi"" disease
`
`•
`
`42 crossed overtoabiraterone acetate group•
`
`1
`
`93 crossed over to abiraterone acetate group
`35ongolng
`58 discontinued
`20due to progressive disease
`
`I 51 crossed over to abiraterone
`acetate groupt
`
`•
`
`546 assigned to ablraterone a<:etate plus prednisone
`546 in ITT population
`4 did not receive stiJdy drogs
`166ongoing
`376discontinued
`283 due to progressive disease
`5421n safety population
`
`l
`
`166 intheabirateroneacetate group
`123ongoing
`43 discontinued
`27 due to progressi"" disease
`
`1
`
`123 in abiraterone acetate group
`4longolng
`81 discontinued
`56 due to progressive disease
`
`figurd:Trialprvfile
`After interim analysis 2, the protocol was amended to allow patients receiving placebo plus prednisone (amendment 3) or tllose who were discontinued from placebo plus prednisone but continuing
`in long-term follow-up (amendment4), to cross !M!rtotheabiraterone acetate plus prednisone group. •under amendment 4,July 9, 2012. tUnder amendment 3,April2, 2012.
`
`154
`
`www.thelancet.com/oncology Vol16 February 2015
`
`

`

`Articles I
`
`Abirllterone acetate Plrocebo group
`(n-542)
`group (n-546)
`
`365(67'11>)
`
`435 (8(M(.)
`
`69(13~)
`100 (18%)
`311 (57%)
`87(16%)
`42(8%)
`20 (4%)
`45(8%)
`
`238(44~)
`105(19%)
`331(61%)
`
`54(1~)
`
`68(13%)
`7(1'11o)
`32 (6'1!>)
`
`Patients with subsequent
`therapy
`Abir.rterone acetate
`Cabazitaxel
`Docetaxel
`Enzalutamide
`Ketoconazole
`Radium-223
`Sipuleucei-T
`
`Data are n (%).
`
`TaW. 1: Subsequent thenlp)' for prosbte c.na~r
`
`Number of
`expected deaths
`{%of expected)
`
`HR(95'11oCI)
`
`pwlue
`
`Interim analysis 1•
`Interim analysis 2t
`Interim analysis 3*
`Final analysis§
`
`98(13~)
`333 (43'1!>)
`
`434(56~)
`741 (96%)
`
`1·08 (0·7H·61)
`0.75 (0-61-0·93)
`0.79 (0·66-0·95)
`o-81 (0-70-0-93)
`
`0·69
`0·0097
`0·015
`0-0033
`
`HR• hazard ratio. •Efficacy boundary HR0-34, nominal slgnifiGJru lovol
`a<0-0001. tEfficacy boundary HR o-67, nominal significanat level a-o-ooo8.
`tEfficacyboundary HR 0·75. nominal significance 1...,.,1 <~=0.0035. SEfficacy
`boundary HR 0-86, nominal slgnlficancelfiWI cz-0.038.
`
`Tcdlle 2: Ovt!rall survival at int.rim Malysis 1, int.rim an~ 2. interim
`analysis 3. and final Malysis
`
`Results
`1088 patients were randomly assigned to receive study
`treatment between April 28, 2009, and June 23, 2010
`(figure 1); treatment groups were well balanced.'·10 The
`clinical cutoff date for the preplanned final analysis was
`March 31, 2014. At the time of the final analysis, treatment
`was ongoing for 42 (8%) patients in the abiraterone
`acetate group and for no patients in the placebo group. At
`the final analysis, 238 (44%) patients from the placebo
`group had subsequently received abiraterone acetate plus
`prednisone (table 1). Of these 238 patients, 93 crossed
`over from receiving prednisone to abiraterone acetate
`plus prednisone per the protocol amendment, with the
`remaining 145 patients receiving abiraterone acetate plus
`prednisone as subsequent therapy, independent of study
`amendments. Of the 93 patients who crossed over per
`the protocol amendment, 51 crossed over directly from
`one group to the other; 42 patients had discontinued
`prednisone alone and may have received subsequent
`prostate cancer therapy before receiving abiraterone
`acetate plus prednisone. The most common reason for
`discontinued
`treatment was disease progression
`(366 [68%] patients in the abiraterone acetate group and
`370 [69%] in the placebo group); adverse events were the
`second most common reason (50 [9%] and 33 [6%];
`appendix). Drug-related adverse events
`leading to
`treatment discontinuation occurred in 35 (7%) of
`542 patients in the abiraterone acetate group and 23 (4%)
`of 540 patients in the placebo group. At the time of the
`final analysis, the median duration of treatment was
`
`Median ovt!rallourvMol
`-
`Abiraterone acetate plus pll!dnisone 34-7 months (95'16 (132-7-36-8)
`-
`Placebo plus prednisone 30·3 months (95'16 Cl28·7-33-3)
`
`80
`
`l
`
`60 1
`1 40
`
`20
`
`0
`
`0
`
`HR 0-81 (95'16 Cl 0-70-0·93)
`p=0-0033
`
`3
`
`6
`
`9
`
`12
`
`15
`
`18
`
`21
`
`24
`
`30
`27
`33
`Time (months)
`
`36
`
`39
`
`42
`
`45
`
`48
`
`51
`
`54
`
`57
`
`60
`
`Numberlltriok
`Ablraterone 546 538
`acetate plus
`pll!dnlsone
`Placebo plus 542
`pll!dnlsone
`
`534
`
`525
`
`504 483
`
`453
`
`422
`
`394 359
`
`330
`
`296
`
`273
`
`235
`
`218
`
`202
`
`189
`
`118
`
`59
`
`15
`
`509 493 466 438
`
`401
`
`363
`
`322
`
`292
`
`261
`
`227
`
`201 1]6 148
`
`132
`
`84
`
`42
`
`10
`
`0
`
`1
`
`0
`
`0
`
`Figure 2: Kaplan-Meier curve of IM!rallourvival
`Efficacy analyses were done in the intention-to-treat populations (ie, all patients assigned to abiraterone acetate or placebo), inespective of subsequent crossover.
`
`www.thelancet.mm/orKOiogy Vol16 February 2015
`
`155
`
`

`

`I Articles
`
`Allp~tienb
`Baseline ECOG
`0
`1
`Baseline BPI-SF
`0-1
`2-3
`Bone metastasis only at entl)'
`Yes
`No
`Age(year5)
`<65
`~65
`
`~75
`Baseline PSAabove median
`Yes
`No
`Baseline LDH above median
`Yes
`No
`Baseline ALJC-P ibove median
`Yes
`No
`Region
`North America
`Other
`
`Modian {months)
`Ablraterone acetate
`plus prednisone
`34-7 !32-7-36·8)
`
`Placebo plus
`prednisone
`30·3 {28·7-33-3)
`
`35-4 (33-7-39·0)
`27-9 (24-6-34-4)
`
`32·0 (29·9-35·0)
`26·4{22-3-30.5)
`
`38-1 {35·0-41·9)
`26-4 (24·4-28·8)
`
`33-4 (30·1-37·3)
`27-4 (22-8-30·9)
`
`38·9 {34-9-45·2)
`31-6 {27-8-34·5)
`
`34·1 {30·1-39·1)
`29·0 (26·0-30·9)
`
`34·5 (31·5-41·7)
`34·7 (31·2-36-8)
`29·3 (26-1-34·5)
`
`30·2 (27·9-36·9)
`30-8 (27·3-33·6)
`25·9 (21..j.-30.0)
`
`28·5 (26+32·5)
`43·1 {36·7-50·0)
`
`25·8 (23-1-28-4)
`34·4 {31·2-38-4)
`
`31-2 (27-3--34·3)
`38·3 {34-5-44-2)
`
`24·8 (21·5-28-6)
`35-8 (32-7-38·8)
`
`28-6 (26+32-3)
`44·5 (37·4-50·4)
`
`26·8 (23·2-31·7)
`33-2 {30.Q-37·6)
`
`37·0 {33·5-40-6)
`33-2 (28·5-35·4)
`
`31-2 (28-7-34·9)
`30·1 {27-2-33-6)
`
`___._ -• -•
`___....__ -•
`
`------
`-------
`___....__
`----------
`---------
`-------
`_____.___
`---------
`
`Huani mio {95% Cl)
`
`Events,IN
`Abiraterone acetate
`plus prednbone
`
`0·81 {0.70-0·93)
`
`3541546
`
`Placebo plus
`prednisone
`
`387/542
`
`0·79 {0-66~·93)
`0-87(0-65-1-16)
`
`0·77 (0·64-0·93)
`0·97 (0·75-1-27)
`
`0·78 (0-62-0-97)
`0-83 (0·69-1·00)
`
`0-78 (0·59-1·03)
`0-81 (0-69-0-96)
`0·79 (0-61-1-10)
`
`0·86 (0·71-1~)
`0·72 (O·S8-<J.90)
`
`0·74 (0-61~·90)
`0-85 (0·69-Hl5)
`
`0-92 (0-7&-1-11)
`0-68 (0·5~·85)
`
`0·74 (0-61~·91)
`0·90 (0·73-1-11)
`
`261/416
`93/130
`
`223/370
`100/129
`
`147/238
`207/3o8
`
`89/135
`265/411
`125/185
`
`208/282
`146/264
`
`192/278
`162/268
`
`211/279
`143/267
`
`184/297
`170/249
`
`292/414
`95/128
`
`233/346
`120/147
`
`162/241
`225/301
`
`111/155
`2761387
`125/165
`
`206/260
`181/282
`
`203/259
`184/283
`
`201/256
`186/286
`
`198/275
`189/267
`
`0·2
`
`.,____
`
`0·75
`
`Favour5 ibiraterone acetate Favour5 placebo plus
`plus p111dnlsone
`prednisone
`
`F/guN 3: Subgroup analyses of overall survival
`ECOG-Eastem Cooperative Oncology Group. BPI-SF-brlefpaln lnvental)'-5hortfarm. PSA-prasta~eclfic antigen. LDH-Iactate dehydragenase.ALK-P-allcallne phosphatase. Efficacy analyses were
`dane in the intention-to-treat populations (ie, all patients assigned to abiraterone acetate or placebo), irrespective of subsequent crossover.
`
`13 · 8 months (IQR 8 · 3-27 ·4) with abiraterone acetate
`plus prednisone and 8·3 months (IQR 3·8-16·6) with
`placebo and prednisone. Dose reductions occurred in 38
`(7%) of 542 patients in the abiraterone acetate group and
`10 (2%) of 540 patients in the placebo group. Subsequent
`therapy was commonly used in both groups (table 1).
`Docetaxel was the most common subsequent therapy
`(table 1).
`Three interim analyses and a final analysis were
`planned, with early analyses not crossing
`the
`prespecified efficacy boundary (table 2). With a median
`follow-up of 49-2 months (IQR 47-0--51-8), the final
`analysis of overall survival was performed after
`741 deaths (96% of 773 expected deaths). The final
`analysis was done at this juncture due to the slowing
`down of the death events at the planned analysis time
`point and additional death events were not expected to
`alter the conclusion at 100% of expected deaths. Fewer
`deaths occurred in the abiraterone acetate group than in
`the placebo group (354 [65%] of 546 patients vs 387 [71%]
`of 542 patients). There was a significant decrease in the
`
`risk of death in the abiraterone acetate group compared
`with the placebo group (hazard ratio [HR] 0·81, 95% CI
`0·7{)....{)·93; p~0·0033; figure 2, table 2). Median overall
`survival was 34·7 months (95% CI 32·7-36·8) in the
`abiraterone acetate group and 30·3 months (28·7-33·3)
`in the placebo group. The effect of abiraterone acetate
`was consistent across all prespecified subgroups
`(figure 3). After adjusting for the crossover effect using
`the IPE method, the risk of death was still lower in the
`abiraterone acetate group than in the placebo group,
`and the decrease was greater than without the
`adjustment (HR 0·74, 95% CI 0·6{)....{)·88).
`In a multivariate analysis correcting for variations in
`baseline prognostic factors, treatment with abiraterone
`acetate plus prednisone resulted in a significantly
`decreased risk of death compared with placebo plus
`prednisone (HR 0·79, 95% Cl 0·68-0·91; p=0·0013).
`Baseline
`PSA,
`lactate
`dehydrogenase,
`alkaline
`phosphatase, haemoglobin, bone metastases, and age
`were all significant prognostic factors for overall survival
`but ECOG performance status score was not (appendix).
`
`156
`
`www.thelancet.com/oncolagy Vol16 February 2015
`
`

`

`Articles I
`
`Median time to opiate use
`Ablraterone ao!tatl! plu' prednisone 33·4 month' (95'11 (130·2-39·8)
`-
`-
`Ploceboplus predni5011e 23-4 months (95% (120·3-27·5)
`
`30
`27
`33
`Time (months)
`
`36
`
`39
`
`42
`
`45
`
`48
`
`51
`
`54
`
`57
`
`60
`
`100
`
`80
`
`6o
`
`40
`
`20
`
`E
`~
`.~ g.
`
`~
`0
`.r;
`·~
`~
`~
`
`0
`
`0
`
`HR 0·72 (95"- Cl 0·61..0·85)
`p<O·OOOt
`
`3
`
`6
`
`9
`
`12
`
`15
`
`18
`
`21
`
`24
`
`Number at risk
`Ahirilterone 546 519
`acetate plus
`prednisone
`Placebo plus 542
`prednisonl!!
`
`500
`
`495 454 407 364 328
`
`297
`
`263
`
`244
`
`219
`
`192 169 162 143
`
`128
`
`74
`
`35
`
`442 406 365
`
`317
`
`273
`
`237
`
`208 186 168 141
`
`121 108
`
`97
`
`as
`
`56
`
`25
`
`9
`
`6
`
`0
`
`0
`
`0
`
`F'f9'Ure.f: Time to use of opiate$ for pain from prostate cancer
`Analysis done with the use of a stratified log-rank test according to baseline ECOG perfomnance status (0 vsl). Analyses were done in the intention-to-tneat
`populations (ie, all patients assigned to abiraterone acetate or placebo), irrespective of subsequent crossover. ECOG=Eastem Cooperative Oncology Group.
`
`Abllllterone Ketate P!Kebo group•
`group (n-542)
`(n•540)
`
`541 {10011.)
`290(54%)
`208(38'11)
`69 (13'11)
`
`524(97%)
`236(44%)
`148 {27'11)
`52 (10'16)
`
`24(4'11.)
`
`15(3'11)
`
`Arry adverse £'\ll!nt
`Gr.ule 3 or 4 adverse event
`Arry serious adverse event
`Adverse everrt leading to
`discontinuation
`Adverse everrt leading to death
`
`Dati are n ('11). ·~ trOSSO'm'.
`
`TaiJ/e 3: Adverse events
`
`Consistent with interim analyses, abiraterone acetate
`plus prednisone decreased the risk of time to opiate use
`for prostate cancer-related pain compared with placebo
`plus prednisone at this final analysis (HR 0-72,95% CI
`0·61-0·85; p<0·0001). Median time to opiate use
`for prostate cancer-related pain was 33 · 4 months
`(95% CI 30-2-39-8) in the abiraterone acetate group
`versus 23 -4 months (95% CI 20 · 3-27 · 5) in the placebo
`group (figure 4).
`Adverse events at the time of the final analysis are
`summarised in table 3. These data were similar to those
`previously reported for the second interim analysis,' after
`nearly 27 months of additional follow-up. At the time of
`final analysis, adverse events of special interest, including
`events related to mineralocorticoid excess, were more
`common in the abiraterone acetate group than in the
`
`www.thelancet.com/oncology Vol16 FebrLNLry 2015
`
`placebo group (table 4). Most were of grade 1 or grade 2
`in severity (table 4). Grade 3 or 4 adverse events of special
`interest reported with abiraterone acetate plus prednisone
`at the final analysis were similar to those reported at the
`second interim analysis.lD The most common adverse
`events in the final analysis resulting in death in the
`abiraterone acetate group were disease progression and
`general physical health deterioration as a sign of clinical
`progression in three (1%) and three (1%) patients,
`respectively. No treatment-related deaths occurred. There
`was no unexpected toxicity in the prespecified subset of
`patients who crossed over from placebo plus prednisone
`to abiraterone acetate plus prednisone (data not shown).
`
`Discussion
`In this final analysis of the COU-AA-302 phase 3 trial,
`overall survival for men with chemotherapy-naive
`metastatic castration-resistant prostate cancer was signifi(cid:173)
`cantly longer with abiraterone acetate and prednisone
`than with placebo and prednisone, meeting the protocol(cid:173)
`specified criterion for statistical significance. Thus both
`coprimary endpoints-radiographic progression-free
`survival and overall survival-have been shown to be
`significantly improved by the addition of abiraterone
`acetate to pred.nisone.'-10 There were no notable changes
`in the safety profile of abiraterone acetate plus prednisone
`since the previously reported interim analyses.'·10
`Regulatory approval for the use of abiraterone acetate
`in combination with prednisone in chemotherapy-naive
`
`

`

`I Articles
`
`Abiraterone aatategroup (n• 542)
`
`Gradesl-2
`
`161(30'lfi)
`87(16'lfi)
`104(19%)
`81(15%)
`20 (4'lfi)
`40 {7%)
`
`47(~)
`
`Grade3
`
`6(1'lfi)
`12(2'lfi)
`25 (5%)
`35 (6%)
`8 (1%)
`28 (5%)
`18 (3'1)
`
`Grade4
`
`O(O'lfi)
`2 (<1%)
`O(O'lfi)
`6 (1%)
`2 (<l'lfi)
`4(<1%)
`O(O'lfi)
`
`GradeS
`
`O(O'lfi)
`0(0%)
`0(0%)
`4(<1%)
`1(<1%)
`0(0%)
`0(0'1)
`
`Placebo group (n• 540)*
`
`Gradesl-2
`
`Grade3
`
`123(23%)
`59 (11%)
`57{11'lfo)
`73 (14%)
`22 (4%)
`23(4%)
`21 (4'1)
`
`8 (1'lfi)
`10(2%)
`17 (3%)
`17 (3%)
`5(<1%)
`3(<1%)
`5(<1'1)
`
`Grade4
`
`1 (<1'lfi)
`O(O'lfi)
`O(O'lfi)
`3 (<1%)
`O(O'lfi)
`1 (<1%)
`O(O'lfi)
`
`GradeS
`
`0(0%)
`0(0%)
`0{0%)
`3(<1'11.)
`0(0%)
`0(0%)
`0(0'1)
`
`Fluid retention/oedema
`Hypolcalaemia
`Hypertension
`Cardiac disorders
`Atrial fibrillation
`ALT increased
`AST increased
`
`Data are n (%). ALT -alanine aminotransferase. AST -aspartate aminotransferase. •Before cro5SOI/el.
`
`Table4: Adverse events of spedallnterest
`
`patients15 was granted in many countries on the basis of
`radiographic progression-free survival and a robust
`association of radiographic progression-free survival
`with overall survival.16 The absence of a significant
`difference in overall survival at the interim analyses
`could be partly attributed to the relatively low number of
`events, or also due to the use of an active control
`(approximately 29% of patients treated with prednisone
`experienced a <!:50% decline in PSA)' rather than a true
`placebo, which might have delayed the separation of the
`survival curves. Nevertheless, the demonstration of a
`difference in overall survival at the final analysis is
`noteworthy as it was observed despite a high proportion
`of patients in the placebo group receiving subsequent
`therapy with abiraterone acetate as well as with docetaxel.
`These observations occurred despite early unblinding
`and therefore support continued data collection rather
`than study termination.
`Further, our findings confirm that the effect of
`abiraterone acetate on overall survival is not dependent
`on, or a function of, prior chemotherapy and was
`consistently observed across predefined subgroups. In
`post-hoc exploratory analysis of patients from COU(cid:173)
`AA-301 and COU-AA-302, Gleason score at initial
`diagnosis {<8 or <!:8) was not predictive of the effect of
`abiraterone acetate, with both groups showing benefit
`irrespective of the Gleason scoreY In another post-hoc
`study, the effect of abiraterone acetate was generally
`observed irrespective of duration of previous androgen
`deprivation therapy in patients from COU-AA-30111 and
`similarly in COU-AA-302 patients (unpublished data). In
`aggregate, the clinical and statistical importance of these
`findings strengthens the rationale for use of abiraterone
`acetate early in the clinical course of metastatic castration(cid:173)
`resistant prostate cancer.
`To the best of our knowledge, the median overall
`survival reported here in the abiraterone acetate plus
`prednisone group is the longest reported to date for
`patients with metastatic castration-resistant prostate
`cancer (>34 months; panel)/ The median duration of
`overall survival noted here also compar