Articles
`
`Abiraterone acetate plus prednisone versus placebo plus
`prednisone in chemotherapy-naive men with metastatic
`castration-resistant prostate cancer (COU-AA-302):
`fi nal overall survival analysis of a randomised, double-blind,
`placebo-controlled phase 3 study
`
`Charles J Ryan, Matthew R Smith, Karim Fizazi, Fred Saad, Peter F A 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, Johann S de Bono, Thomas W Griffi n, Peter De Porre,
`Margaret K Yu, Youn C Park, Jinhui Li, Thian Kheoh, Vahid Naini, Arturo Molina, Dana E Rathkopf, for the COU-AA-PQR Investigators*
`
`Summary
`Background Abiraterone acetate plus prednisone signifi cantly 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 prespecifi ed fi nal analysis of the trial, assessing the
`eff ect of abiraterone acetate plus prednisone on overall survival, time to opiate use, and use of other subsequent
`therapies.
`
`Methods In this placebo-controlled, double-blind, randomised phase 3 study, 1088 asymptomatic or mildly
`symptomatic patients with chemotherapy-naive prostate cancer stratifi ed 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 NCT00887198.
`
`Findings At a median follow-up of 49·2 months (IQR 47·0–51·8), 741 (96%) of the prespecifi ed 773 death events for
`the fi nal analysis had been observed: 354 (65%) of 546 patients in the abiraterone acetate group and 387 (71%) of
`542 in the placebo group. 238 (44%) patients initially receiving prednisone alone subsequently received abiraterone
`acetate plus prednisone as crossover per protocol (93 patients) or as subsequent therapy (145 patients). Overall,
`365 (67%) patients in the abiraterone acetate group and 435 (80%) in the placebo group received subsequent treatment
`with one or more approved agents. Median overall survival was signifi cantly 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=0·0033). 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%] of 540 patients in the placebo group), increased alanine
`aminotransferase (32 [6%] vs four [<1%]), and hypertension (25 [5%] vs 17 [3%]).
`
`Interpretation In this randomised phase 3 trial with a median follow-up of more than 4 years, treatment with
`abiraterone acetate prolonged overall survival compared with prednisone alone by a margin that was both clinically
`and statistically signifi cant. These results further support the favourable safety profi le of abiraterone acetate in
`patients with chemotherapy-naive metastatic castration-resistant prostate cancer.
`
`Funding Janssen Research & Development.
`
`Introduction
`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
`survival was docetaxel.1,2 Over the past 4 years, fi ve
`therapeutics with demonstrated survival benefi t in
`randomised clinical studies have become available, and
`are commonly used in sequence.3–11 Given the chronicity
`and heterogeneity of metastatic castration-resistant
`
`prostate cancer, administration of such subsequent
`therapies may confound the measurement of the eff ect
`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
`signifi cant improvement in survival, compared with
`placebo plus prednisone, for patients with metastatic
`castration-resistant prostate cancer with progression of
`
`Amerigen Exhibit 1110
`Amerigen v. Janssen IPR2016-00286
`
`www.thelancet.com/oncology Vol 16 February 2015
`
`Lancet Oncol 2015; 16: 152–60
`
`Published Online
`January 16, 2015
`http://dx.doi.org/10.1016/
`S1470-2045(14)71205-7
`
`See Comment page 119
`
`*Additional investigators listed
`in the appendix
`
`Helen Diller Family
`Comprehensive Cancer Center,
`University of California
`San Francisco, San Francisco,
`CA, USA (Prof C J Ryan MD,
`Prof E J Small MD); Harvard
`Medical School and
`Massachusetts General
`Hospital, Boston, MA, USA
`(Prof M R Smith MD); Institut
`Gustave Roussy, University
`of Paris Sud, Villejuif, France
`(Prof K Fizazi MD); University of
`Montréal, Montréal, Québec,
`Canada (Prof F Saad MD);
`Radboud University Medical
`Centre, Nijmegen, Netherlands
`(Prof P F A Mulders MD);
`San Camillo and Forlanini
`Hospitals, Rome, Italy
`(C N Sternberg MD); Charité
`Berlin, Berlin, Germany
`(Prof K Miller MD); MD
`Anderson Cancer Center,
`Houston, TX, USA
`(Prof C J Logothetis MD);
`Carolina Urologic Research
`Center, Atlantic Urology Clinics,
`Myrtle Beach, SC, USA
`(N D Shore MD); Vall d’Hebron
`University Hospital and Vall
`d’Hebron Institute of
`Oncology, Barcelona, Spain
`(J Carles MD); University of
`Colorado Cancer Center and
`University of Colorado School
`of Medicine, Aurora, CO, USA
`(T W Flaig MD); Dana-Farber
`Cancer Institute, Harvard
`Medical School, Boston, MA,
`USA (M-E Taplin MD);
`University of Washington, Fred
`Hutchinson Cancer Research
`
`152
`
`

`

`Articles
`
`Center, Seattle, WA, USA
`(Prof C S Higano MD); University
`of Western Sydney School of
`Medicine and Ingham
`Institute, Liverpool, Australia
`(Prof P de Souza MB); The
`Institute of Cancer Research
`and the Royal Marsden
`Hospital, Sutton, United
`Kingdom
`(Prof J S de Bono MB ChB);
`Janssen Research &
`Development, Los Angeles, CA,
`USA (T W Griffi n MD, M K Yu MD,
`T Kheoh PhD, V Naini PharmD);
`Janssen Research &
`Development, Beerse, Belgium
`(P De Porre MD); Janssen
`Research & Development,
`Raritan, NJ, USA (Y C Park PhD,
`J Li PhD), Janssen Research &
`Development, Menlo Park, CA,
`USA (A Molina MD); and
`Memorial Sloan Kettering
`Cancer Center, New York, NY,
`USA (D E Rathkopf MD)
`
`Correspondence to:
`Prof Charles J Ryan,
`Genitourinary Medical Oncology
`Program, UCSF Helen Diller
`Family Comprehensive Cancer
`Center, 1600 Divisadero Street,
`San Francisco, CA, 94115, USA
`ryanc@medicine.ucsf.edu
`
`See Online for appendix
`
`disease after administration of chemotherapy.5,6 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.9,10,12 However, at
`the interim analyses, overall survival results did not cross
`the prespecifi ed effi cacy boundary
`for statistical
`signifi cance as defi ned by O’Brien and Fleming.13
`Here, we present the fi nal 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-
`resistant prostate cancer.
`
`Methods
`Study design and participants
`The patient population for this multinational, double-
`blind, randomised, placebo-controlled phase 3 trial has
`been described previously.9,10 Briefl y, patients aged 18 years
`or over with histologically or cytologically confi rmed
`adenocarcinoma of the prostate, prostate-specifi c 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 ng/dL
`(1·7 nmol/L), an Eastern Cooperative Oncology Group
`(ECOG) performance status grade of 0 or 1, with Brief-
`Pain Inventory-Short Form scores of 0–1 (asymptomatic)
`or 2–3 (mildly symptomatic), previous anti-androgen
`therapy followed by documented PSA progression after
`discontinuing the anti-androgen, and haematological and
`chemical laboratory values that met predefi ned 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-
`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
`stratifi ed 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
`
`placebo plus prednisone group and in long-term follow-
`up, investigator assessment that abira terone acetate
`therapy would be safe and benefi cial, not currently
`receiving prostate cancer therapy other than luteinising
`hormone-releasing hormone analogues, no concomitant
`administration of cytotoxic chemotherapy, and ECOG
`performance status of 0, 1, or 2.
`
`Procedures
`Patients
`in the abiraterone acetate group received
`abiraterone acetate (Patheon, Mississauga, Canada) at a
`dose of 1000 mg (administered as four 250 mg tablets) and
`prednisone at a dose of 5 mg 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 fi rst to three tablets (750 mg) daily and, if indicated, a
`second to two tablets (500 mg) 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 fi rst
`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 prespecifi ed visits.
`
`Outcomes
`The coprimary endpoints were radiographic progression-
`free survival and overall survival. Overall survival has
`been reported previously in interim analyses,9,10 and the
`analysis of
`radiographic progression-free survival
`requiring 378 events was fully matured as reported
`previously.9 The focus of this report is an update of overall
`survival from the fi nal analysis and the secondary
`endpoint of time to opiate use for cancer-related pain.
`Long-term safety data are also reported.
`
`Statistical analysis
`A fi nal 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
`
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`

`Articles
`
`Kaplan-Meier method, where patients were censored at
`death. The primary statistical method of comparison for
`the time-to-event endpoints was the stratifi ed log-rank
`test stratifi ed 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 eff ect via the
`iterative parameter estimate (IPE) method14 was done to
`estimate the true treatment eff ect 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 eff ect 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 eff ective
`treatment while the control group is receiving the same
`eff ective treatment at the start of crossover or subsequent
`therapy. An exploratory multivariate analysis for overall
`survival evaluated the potential eff ect of important
`prognostic factors on the treatment eff ect. Based on
`multivariate analysis at the second interim analysis, the
`following signifi cant (univariate, p<0·01) 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. Effi cacy 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
`NCT00887198.
`
`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 fi rst 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 fi delity to the protocol, and statistical
`analysis. CJR had full access to all of the data and the fi nal
`responsibility to submit for publication.
`
`1533 patients assessed for eligibility
`
`445 ineligible at screening
`
`1088 randomised
`
`542 assigned to placebo plus prednisone
`
`542 in ITT population
`
`
`2 did not receive study drugs
`
` 86 ongoing
`
` 454 discontinued
`
`
` 351 due to progressive disease
`
`540 in safety population
`
`86 in the placebo group
`
`58 ongoing
`
`28 discontinued
`
`18 due to progressive disease
`
`7 in placebo group
` 7 discontinued
`
`1 due to progressive disease
`
`546 assigned to abiraterone acetate plus prednisone
`
`546 in ITT population
`
` 4 did not receive study drugs
`
` 166 ongoing
`
` 376 discontinued
`
`
` 283 due to progressive disease
`
`542 in safety population
`
`166 in the abiraterone acetate group
`
`123 ongoing
`
`43 discontinued
`
`27 due to progressive disease
`
`42 crossed over to abiraterone acetate group*
`
`123 in abiraterone acetate group
`
`42 ongoing
`
`81 discontinued
`
`56 due to progressive disease
`
`93 crossed over to abiraterone acetate group
`
`35 ongoing
`
`58 discontinued
`
`20 due to progressive disease
`
`51 crossed over to abiraterone
` acetate group†
`
`Dec 20, 2011
`
`Interim analysis 2
`
`May 22, 2012
`
`Interim analysis 3
`
`March 31, 2014
`Final analysis
`
`Figure ': Trial profi le
`After interim analysis 2, the protocol was amended to allow patients receiving placebo plus prednisone (amendment 3) or those who were discontinued from placebo plus prednisone but continuing
`in long-term follow-up (amendment 4), to cross over to the abiraterone acetate plus prednisone group. *Under amendment 4, July 9, 2012. †Under amendment 3, April 2, 2012.
`
`154
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`

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`
`Results
`1088 patients were randomly assigned to receive study
`treatment between April 28, 2009, and June 23, 2010
`(fi gure 1); treatment groups were well balanced.9,10 The
`clinical cutoff date for the preplanned fi nal analysis was
`March 31, 2014. At the time of the fi nal analysis, treatment
`was ongoing for 42 (8%) patients in the abiraterone
`acetate group and for no patients in the placebo group. At
`the fi nal 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
`fi nal analysis, the median duration of treatment was
`
`Median overall survival
`
`Abiraterone acetate plus prednisone 34·7 months (95% CI 32·7–36·8)
`
`Placebo plus prednisone 30·3 months (95% CI 28·7–33·3)
`
`HR 0·81 (95% CI 0·70–0·93)
`p=0·0033
`
`33
`
`42
`
`51
`
`57
`
`Abiraterone acetate
`group (n=546)
`
`Placebo group
`(n=542)
`
`365 (67%)
`
`435 (80%)
`
`69 (13%)
`
`100 (18%)
`
`311 (57%)
`
`87 (16%)
`
`42 (8%)
`
`20 (4%)
`
`45 (8%)
`
`238 (44%)
`
`105 (19%)
`
`331 (61%)
`
`54 (10%)
`
`68 (13%)
`
`7 (1%)
`
`32 (6%)
`
`Patients with subsequent
`therapy
`
`Abiraterone acetate
`
`Cabazitaxel
`
`Docetaxel
`
`Enzalutamide
`
`Ketoconazole
`
`Radium-223
`
`Sipuleucel-T
`
`Data are n (%).
`
`Table -: Subsequent therapy for prostate cancer
`
`Number of
`expected deaths
`(% of expected)
`
`HR (95% CI)
`
`p value
`
`Interim analysis 1*
`
`98 (13%)
`
`1·08 (0·73–1·61)
`
`0·69
`
`Interim analysis 2†
`
`333 (43%)
`
`0·75 (0·61–0·93)
`
`0·0097
`
`Interim analysis 3‡
`
`434 (56%)
`
`0·79 (0·66–0·95)
`
`0·015
`
`Final analysis§
`
`741 (96%)
`
`0·81 (0·70–0·93)
`
`0·0033
`
`HR=hazard ratio. *Effi cacy boundary HR 0·34, nominal signifi cance level
`α<0·0001. †Effi cacy boundary HR 0·67, nominal signifi cance level α=0·0008.
`‡Effi cacy boundary HR 0·75, nominal signifi cance level α=0·0035. §Effi cacy
`boundary HR 0·86, nominal signifi cance level α=0·038.
`
`Table ': Overall survival at interim analysis 1, interim analysis 2, interim
`analysis 3, and fi nal analysis
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Overall survival (%)
`
`0
`
`3
`
`6
`
`9
`
`12
`
`15
`
`18
`
`21
`
`24
`
`27
`
`30
`
`36
`
`39
`
`45
`
`48
`
`54
`
`60
`
`Time (months)
`
`546
`
`538
`
`525
`
`504
`
`483
`
`453
`
`422
`
`394
`
`359
`
`330
`
`296
`
`273
`
`235
`
`218
`
`202
`
`189
`
`118
`
`59
`
`15
`
`542
`
`534
`
`509
`
`493
`
`466
`
`438
`
`401
`
`363
`
`322
`
`292
`
`261
`
`227
`
`201
`
`176
`
`148
`
`132
`
`84
`
`42
`
`10
`
`0
`
`1
`
`0
`
`0
`
`Number at risk
` Abiraterone
`acetate plus
`prednisone
`Placebo plus
`prednisone
`
`Figure ': Kaplan-Meier curve of overall survival
`Effi cacy analyses were done in the intention-to-treat populations (ie, all patients assigned to abiraterone acetate or placebo), irrespective of subsequent crossover.
`
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`
`All patients
`
`Baseline ECOG
`
` 0
`
` 1
`
`Baseline BPI-SF
`
` 0–1
`
` 2–3
`
`Bone metastasis only at entry
`
` Yes
`
` No
`
`Age (years)
`
` <65
`
` ≥65
`
`Median (months)
`
`Abiraterone acetate
`plus prednisone
`
`Placebo plus
`prednisone
`
`34·7 (32·7–36·8)
`
`30·3 (28·7–33·3)
`
`35·4 (33·7–39·0)
`
`32·0 (29·9–35·0)
`
`27·9 (24·6–34·4)
`
`26·4 (22·3–30·5)
`
`38·1 (35·0–41·9)
`
`33·4 (30·1–37·3)
`
`26·4 (24·4–28·8)
`
`27·4 (22·8–30·9)
`
`38·9 (34·9–45·2)
`
`34·1 (30·1–39·1)
`
`31·6 (27·8–34·5)
`
`29·0 (26·0–30·9)
`
`34·5 (31·5–41·7)
`
`30·2 (27·9–36·9)
`
`34·7 (31·2–36·8)
`
`30·8 (27·3–33·6)
`
`Hazard ratio (95% CI)
`
`Events/N
`
`Abiraterone acetate
`plus prednisone
`
`Placebo plus
`prednisone
`
`0·81 (0·70–0·93)
`
` 354/546
`
` 387/542
`
`0·79 (0·66–0·93)
`
`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)
`
`
`
` 261/416
`
` 93/130
`
`
`
` 223/370
`
` 100/129
`
`
`
` 147/238
`
` 207/308
`
`
`
` 89/135
`
` 265/411
`
` 292/414
`
` 95/128
`
` 233/346
`
` 120/147
`
` 162/241
`
` 225/301
`
` 111/155
`
` ≥75
`
`29·3 (26·1–34·5)
`
`25·9 (21·4–30·0)
`
`0·79 (0·61–1·10)
`
` 125/185
`
`Baseline PSA above median
`
` Yes
`
` No
`
`Baseline LDH above median
`
` Yes
`
` No
`
`Baseline ALK-P above median
`
` Yes
`
` No
`
`Region
`
` North America
`
` Other
`
`28·5 (26·4–32·5)
`
`25·8 (23·1–28·4)
`
`43·1 (36·7–50·0)
`
`34·4 (31·2–38·4)
`
`31·2 (27·3–34·3)
`
`24·8 (21·5–28·6)
`
`38·3 (34·5–44·2)
`
`35·8 (32·7–38·8)
`
`28·6 (26·4–32·3)
`
`26·8 (23·2–31·7)
`
`44·5 (37·4–50·4)
`
`33·2 (30·0–37·6)
`
`37·0 (33·5–40·6)
`
`31·2 (28·7–34·9)
`
`33·2 (28·5–35·4)
`
`30·1 (27·2–33·6)
`
`0·86 (0·71–1·04)
`
`0·72 (0·58–0·90)
`
`0·74 (0·61–0·90)
`
`0·85 (0·69–1·05)
`
`0·92 (0·76–1·11)
`
`0·68 (0·55–0·85)
`
`0·74 (0·61–0·91)
`
`0·90 (0·73–1·11)
`
` 208/282
`
` 146/264
`
` 192/278
`
` 162/268
`
` 211/279
`
` 143/267
`
` 184/297
`
` 170/249
`
` 276/387
`
` 125/165
`
` 206/260
`
` 181/282
`
` 203/259
`
` 184/283
`
` 201/256
`
` 186/286
`
` 198/275
`
` 189/267
`
`0·2
`
`0·75
`
`1·5
`
`Favours abiraterone acetate
`plus prednisone
`
`Favours placebo plus
`prednisone
`
`Figure ': Subgroup analyses of overall survival
`ECOG=Eastern Cooperative Oncology Group. BPI-SF=brief pain inventory—short form. PSA=prostate-specifi c antigen. LDH=lactate dehydrogenase. ALK-P=alkaline phosphatase. Effi cacy analyses were
`done 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 fi nal analysis were
`planned, with early analyses not crossing
`the
`prespecifi ed effi cacy boundary (table 2). With a median
`follow-up of 49·2 months (IQR 47·0–51·8), the fi nal
`analysis of overall survival was performed after
`741  deaths (96% of 773 expected deaths). The fi nal
`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 signifi cant decrease in the
`
`risk of death in the abiraterone acetate group compared
`with the placebo group (hazard ratio [HR] 0·81, 95% CI
`0·70–0·93; p=0·0033; fi gure 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 eff ect of abiraterone acetate
`was consistent across all prespecifi ed subgroups
`(fi gure 3). After adjusting for the crossover eff ect 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 0·60–0·88).
`In a multivariate analysis correcting for variations in
`baseline prognostic factors, treatment with abiraterone
`acetate plus prednisone resulted in a signifi cantly
`decreased risk of death compared with placebo plus
`prednisone (HR 0·79, 95% CI 0·68–0·91; p=0·0013).
`Baseline PSA,
`lactate
`dehydrogenase,
`alkaline
`phosphatase, haemo globin, bone metastases, and age
`were all signifi cant prognostic factors for overall survival
`but ECOG performance status score was not (appendix).
`
`156
`
`www.thelancet.com/oncology Vol 16 February 2015
`
`

`

`Articles
`
`Median time to opiate use
`
`Abiraterone acetate plus prednisone 33·4 months (95% CI 30·2–39·8)
`
`Placebo plus prednisone 23·4 months (95% CI 20·3–27·5)
`
`HR 0·72 (95% CI 0·61–0·85)
`p<0·0001
`
`3
`
`6
`
`9
`
`12
`
`15
`
`18
`
`21
`
`24
`
`27
`
`30
`
`33
`
`36
`
`39
`
`42
`
`45
`
`48
`
`51
`
`54
`
`57
`
`60
`
`Time (months)
`
`100
`
`80
`
`60
`
`40
`
`20
`
`Patients without opiate use (%)
`
`0
`
`0
`
`Number at risk
` Abiraterone
`acetate plus
`prednisone
`Placebo plus
`prednisone
`
`546
`
`519
`
`495
`
`454
`
`407
`
`364
`
`328
`
`297
`
`263
`
`244
`
`219
`
`192
`
`169
`
`162
`
`143
`
`128
`
`74
`
`35
`
`542
`
`500
`
`442
`
`406
`
`365
`
`317
`
`273
`
`237
`
`208
`
`186
`
`168
`
`141
`
`121
`
`108
`
`97
`
`85
`
`56
`
`25
`
`9
`
`6
`
`0
`
`1
`
`0
`
`0
`
`Figure ,: Time to use of opiates for pain from prostate cancer
`Analysis done with the use of a stratifi ed log-rank test according to baseline ECOG performance status (0 vs 1). Analyses were done in the intention-to-treat
`populations (ie, all patients assigned to abiraterone acetate or placebo), irrespective of subsequent crossover. ECOG=Eastern Cooperative Oncology Group.
`
`Any adverse event
`
`Grade 3 or 4 adverse event
`
`Any serious adverse event
`
`Adverse event leading to
`discontinuation
`
`Abiraterone acetate
`group (n=542)
`
`Placebo group*
`(n=540)
`
`541 (100%)
`
`290 (54%)
`
`208 (38%)
`
`69 (13%)
`
`524 (97%)
`
`236 (44%)
`
`148 (27%)
`
`52 (10%)
`
`Adverse event leading to death
`
`24 (4%)
`
`15 (3%)
`
`Data are n (%). *Before crossover.
`
`Table &: 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 fi nal 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 (fi gure 4).
`Adverse events at the time of the fi nal analysis are
`summarised in table 3. These data were similar to those
`previously reported for the second interim analysis,9 after
`nearly 27 months of additional follow-up. At the time of
`fi nal analysis, adverse events of special interest, including
`events related to mineralocorticoid excess, were more
`common in the abiraterone acetate group than in the
`
`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 fi nal analysis were similar to those reported at the
`second interim analysis.10 The most common adverse
`events in the fi nal 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 prespecifi ed subset of
`patients who crossed over from placebo plus prednisone
`to abiraterone acetate plus prednisone (data not shown).
`
`Discussion
`In this fi nal analysis of the COU-AA-302 phase 3 trial,
`overall survival for men with chemotherapy-naive
`metastatic castration-resistant prostate cancer was signifi -
`cantly longer with abiraterone acetate and prednisone
`than with placebo and prednisone, meeting the protocol-
`specifi ed criterion for statistical signifi cance. Thus both
`coprimary endpoints—radiographic progression-free
`survival and overall survival—have been shown to be
`signifi cantly improved by the addition of abiraterone
`acetate to prednisone.9,10 There were no notable changes
`in the safety profi le of abiraterone acetate plus prednisone
`since the previously reported interim analyses.9,10
`Regulatory approval for the use of abiraterone acetate
`in combination with prednisone in chemotherapy-naive
`
`www.thelancet.com/oncology Vol 16 February 2015
`
`157
`
`

`

`Articles
`
`Abiraterone acetate group (n=542)
`
`Placebo group (n=540)*
`
`Grades 1–2
`
`Grade 3
`
`Grade 4
`
`Grade 5
`
`Grades 1–2
`
`Grade 3
`
`Grade 4
`
`Grade 5
`
`Fluid retention/oedema
`
`161 (30%)
`
`Hypokalaemia
`
`Hypertension
`
`Cardiac disorders
`
`Atrial fi brillation
`
`ALT increased
`
`AST increased
`
`87 (16%)
`
`104 (19%)
`
`81 (15%)
`
`20 (4%)
`
`40 (7%)
`
`47 (9%)
`
`6 (1%)
`
`12 (2%)
`
`25 (5%)
`
`35 (6%)
`
`8 (1%)
`
`28 (5%)
`
`18 (3%)
`
`0 (0%)
`
`2 (<1%)
`
`0 (0%)
`
`6 (1%)
`
`2 (<1%)
`
`4 (<1%)
`
`0 (0%)
`
`0 (0%)
`
`0 (0%)
`
`0 (0%)
`
`4 (<1%)
`
`1 (<1%)
`
`0 (0%)
`
`0 (0%)
`
`123 (23%)
`
`59 (11%)
`
`57 (11%)
`
`73 (14%)
`
`22 (4%)
`
`23 (4%)
`
`21 (4%)
`
`8 (1%)
`
`10 (2%)
`
`17 (3%)
`
`17 (3%)
`
`5 (<1%)
`
`3 (<1%)
`
`5 (<1%)
`
`1 (<1%)
`
`0 (0%)
`
`0 (0%)
`
`3 (<1%)
`
`0 (0%)
`
`1 (<1%)
`
`0 (0%)
`
`0 (0%)
`
`0 (0%)
`
`0 (0%)
`
`3 (<1%)
`
`0 (0%)
`
`0 (0%)
`
`0 (0%)
`
`Data are n (%). ALT=alanine aminotransferase. AST=aspartate aminotransferase. *Before crossover.
`
` Table &: Adverse events of special interest
`
`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 signifi cant
`diff erence 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)9 rather than a true
`placebo, which might have delayed the separation of the
`survival curves. Nevertheless, the demonstration of a
`diff erence in overall survival at the fi nal 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 fi ndings confi rm that the eff ect of
`abiraterone acetate on overall survival is not dependent
`on, or a function of, prior chemotherapy and was
`consistently observed across predefi ned subgroups. In
`post-hoc exploratory analysis of patients from COU-
`AA-301 and COU-AA-302, Gleason score at initial
`diagnosis (<8 or ≥8) was not predictive of the eff ect of
`abiraterone acetate, with both groups showing benefi t
`irrespective of the Gleason score.17 In another post-hoc
`study, the eff ect of abiraterone acetate was generally
`observed irrespective of duration of previous androgen
`deprivation therapy in patients from COU-AA-30118 and
`similarly in COU-AA-302 patients (unpublished data). In
`aggregate, the clinical and statistical importance of these
`fi ndings strengthens the rationale for use of abiraterone
`acetate early in the clinical course of metastatic castration-
`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).7 The median duration of
`overall survival noted here also compares favourably with
`that observed in the PREVAIL trial of a generally similar
`
`chemotherapy-naive patient population treated with
`enzalutamide.3 However, in the absence of head-to-head
`trials, these data cannot be used to inform which agent
`should be used fi rst in sequential therapy. The d