E U R O P E A N U R O L O G Y 6 6 ( 2 0 1 4 ) 8 1 5 – 8 2 5
`
`a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m
`
`j o u r n a l h o m e p a g e : w w w . e u r o p e a n u r o l o g y . c o m
`
`Platinum Priority – Prostate Cancer
`Editorial by Daniel Suzman and Mario Eisenberger on pp. 826–828 of this issue
`
`Updated Interim Efficacy Analysis and Long-term Safety of
`Abiraterone Acetate in Metastatic Castration-resistant Prostate
`Cancer Patients Without Prior Chemotherapy (COU-AA-302)
`
`Dana E. Rathkopf a,*, Matthew R. Smith b, Johann S. de Bono c, Christopher J. Logothetis d,
`Neal D. Shore e, Paul de Souza f, Karim Fizazi g, Peter F.A. Mulders h, Paul Mainwaring i,
`John D. Hainsworth j, Tomasz M. Beer k, Scott North l, Yves Fradet m, Hendrik Van Poppel n,
`Joan Carles o, Thomas W. Flaig p, Eleni Efstathiou d, Evan Y. Yu q, Celestia S. Higano q,
`Mary-Ellen Taplin r, Thomas W. Griffin s, Mary B. Todd t, Margaret K. Yu s, Youn C. Park t,
`Thian Kheoh s, Eric J. Small u, Howard I. Scher a, Arturo Molina v, Charles J. Ryan u, Fred Saad w
`
`a Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA; b Harvard Medical School and Massachusetts General
`Hospital, Boston, MA, USA; c The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK; d MD Anderson Cancer Center,
`Houston, TX, USA; e Carolina Urologic Research Center, Atlantic Urology Clinics, Myrtle Beach, SC, USA; f University of Western Sydney School of Medicine,
`Penrith, Australia; g Institut Gustave Roussy, University of Paris Sud, Villejuif, France; h Radboud University Medical Centre, Nijmegen, The Netherlands;
`i Hematology & Oncology Clinics of Australia, Brisbane, Australia; j Sarah Cannon Research Institute, Nashville, TN, USA; k Oregon Health & Science University
`Knight Cancer Institute, Portland, OR, USA; l Cross Cancer Institute, Edmonton, Alberta, Canada; m Laval University, Que´bec City, Que´bec, Canada; n University
`Hospital Leuven, Leuven, Belgium; o Hospital Universitari Vall d’Hebron, Universitat Auto`noma de Barcelona, Barcelona, Spain; p University of Colorado
`Cancer Center and University of Colorado School of Medicine, Aurora, CO, USA; q University of Washington, Fred Hutchinson Cancer Research Center, Seattle,
`WA, USA; r Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; s Janssen Research & Development, Los Angeles, CA, USA; t Janssen
`Research & Development, Raritan, NJ, USA; u Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA; v Janssen
`Research & Development, Menlo Park, CA, USA; w CRCHUM, University of Montre´al, Montre´al, Que´bec, Canada
`
`Article info
`
`Abstract
`
`Article history:
`Accepted February 24, 2014
`
`Keywords:
`Abiraterone acetate
`Chemotherapy-naive
`Efficacy
`Metastatic castration-resistant
`prostate cancer
`Safety
`
`Background: Abiraterone acetate (an androgen biosynthesis inhibitor) plus prednisone
`is approved for treating patients with metastatic castration-resistant prostate cancer
`(mCRPC). Study COU-AA-302 evaluated abiraterone acetate plus prednisone versus
`prednisone alone in mildly symptomatic or asymptomatic patients with progressive
`mCRPC without prior chemotherapy.
`Objective: Report the prespecified third interim analysis (IA) of efficacy and safety
`outcomes in study COU-AA-302.
`Design, setting, and participants: Study COU-AA-302, a double-blind placebo-controlled
`study, enrolled patients with mCRPC from April 2009 to June 2010. A total of 1088 patients
`were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1).
`Intervention: Patients were randomised 1:1 to abiraterone 1000 mg plus prednisone
`5 mg twice daily by mouth versus prednisone.
`Outcome measurements and statistical analysis: Co–primary end points were radio-
`graphic progression-free survival (rPFS) and overall survival (OS). Median times to event
`outcomes were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95%
`confidence intervals (CIs) were derived using the Cox model, and treatment comparison
`
`* Corresponding author. Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York,
`NY 10065, USA. Tel. +1 646 422 4379; Fax: +1 212 988 0701.
`E-mail address: rathkopd@mskcc.org (D.E. Rathkopf).
`
`http://dx.doi.org/10.1016/j.eururo.2014.02.056
`0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
`
`Amerigen Exhibit 1109
`Amerigen v. Janssen IPR2016-00286
`
`

`
`816
`
`E U R O P E A N U R O L O G Y 6 6 ( 2 0 1 4 ) 8 1 5 – 8 2 5
`
`Please visit
`www.eu-acme.org/
`europeanurology to read and
`answer questions on-line.
`The EU-ACME credits will
`then be attributed
`automatically.
`
`used the log-rank test. The O’Brien-Fleming Lan-DeMets a-spending function was used
`for OS. Adverse events were summarised descriptively.
`Results and limitations: With a median follow-up duration of 27.1 mo, improvement in
`rPFS was statistically significant with abiraterone treatment versus prednisone (median:
`16.5 vs 8.2 mo; HR: 0.52 [95% CI, 0.45–0.61]; p < 0.0001). Abiraterone improved OS
`(median: 35.3 vs 30.1 mo; HR: 0.79 [95% CI, 0.66–0.95]; p = 0.0151) but did not reach the
`prespecified statistical efficacy boundary (a-level: 0.0035). A post hoc multivariate
`analysis for OS using known prognostic factors supported the primary results (HR:
`0.74 [95% CI, 0.61–0.89]; p = 0.0017), and all clinically relevant secondary end points and
`patient-reported outcomes improved. While the post hoc nature of the long-term safety
`analysis is a limitation, the safety profile with longer treatment exposure was consistent
`with prior reports.
`Conclusions: The updated IA of study COU-AA-302 in patients with mCRPC without
`prior chemotherapy confirms that abiraterone delays disease progression, pain, and
`functional deterioration and has clinical benefit with a favourable safety profile, includ-
`ing in patients treated for 24 mo.
`Trial registration: Study COU-AA-302, ClinicalTrials.gov number, NCT00887198.
`Patient summary: The updated results of this ongoing study showed that disease
`progression was delayed in patients with advanced prostate cancer who were treated
`with abiraterone acetate and prednisone, and there was a continued trend in prolonga-
`tion of life compared with patients treated with prednisone alone. Treatment with
`abiraterone acetate and prednisone was well tolerated by patients who were treated for
`>2 yr.
`# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
`
`1.
`
`Introduction
`
`Androgen deprivation therapy is the standard of care for
`advanced prostate cancer (PCa), but patients invariably
`progress to castration-resistant disease despite castration
`levels of serum testosterone (<50 ng/dl) [1,2]. Metastatic
`castration-resistant PCa (mCRPC) represents the lethal form
`of the disease, with, until recently,
`limited treatment
`options and a median survival of <2 yr [3]. Chemotherapy
`provides an overall survival (OS) benefit for patients with
`mCRPC [4–7], but newer treatments with fewer side-effects
`are now available that may be preferable options before
`chemotherapy. Building on an increased understanding of
`the continued relevance of the androgen receptor signalling
`pathway in mCRPC, targeting residual androgen production
`offers great promise as a well-tolerated and effective
`alternative to standard cytotoxic therapies [8–10].
`Abiraterone acetate is the prodrug of abiraterone, a
`specific inhibitor of CYP17 that blocks extragonadal,
`testicular, and tumour androgen biosynthesis [9,11,12]. In
`patients with mCRPC who had received prior docetaxel
`chemotherapy, abiraterone acetate (henceforth abiraterone)
`plus low-dose prednisone improved median OS by 4.6 mo
`(hazard ratio [HR]: 0.74; 95% confidence interval [CI], 0.64–
`0.86; p < 0.0001) compared with placebo plus prednisone
`(henceforth prednisone) [13,14].
`Study COU-AA-302 is evaluating the clinical benefit of
`abiraterone plus prednisone versus prednisone in mildly
`symptomatic or asymptomatic patients with progressive
`mCRPC without prior chemotherapy [15]. Based on a
`preplanned interim analysis (IA) [15], the independent
`data-monitoring committee reviewed the masked efficacy
`and safety outcomes and recommended that the study be
`unblinded and patients be allowed to cross over from the
`prednisone group to receive abiraterone. Subsequently, in
`December 2012, abiraterone therapy received expanded
`regulatory approval in the United States and Europe [16] to
`
`also treat patients with mCRPC prior to receiving chemo-
`therapy. We report the results of the third IA (IA3),
`preplanned at 55% OS events (425 of 773), for study
`COU-AA-302 and provide an update of efficacy and long-
`term safety outcomes.
`
`2.
`
`Patients and methods
`
`COU-AA-302 (NCT00887198) is a phase 3, multinational, randomised,
`
`double-blind, placebo-controlled study being conducted at 151 sites in 12
`
`countries. Patients were enrolled from April 2009 to June 2010; the study is
`
`ongoing. The review boards at all participating institutions approved the
`
`study, which was conducted according to the Declaration of Helsinki, the
`
`International Conference on Harmonisation, and the Guidelines for Good
`
`Clinical Practice. All patients gave written informed consent.
`
`2.1.
`
`Patient population
`
`The study design and primary and secondary efficacy end points have
`
`been previously described in detail for the second IA (IA2) [15] and are
`
`summarised in this paper. The study included male patients aged 18 yr
`with chemotherapy-naive mCRPC, who were medically or surgically
`
`castrated, had tumour progression, and were asymptomatic or mildly
`
`symptomatic, as defined by the Brief Pain Inventory–Short Form
`
`(asymptomatic with scores of 0 or 1 or mildly asymptomatic with
`
`scores of 2–3). Patients with visceral metastases or patients who had
`
`received previous therapy with ketoconazole for >7 d were excluded.
`
`2.2.
`
`Study design
`
`Patients were stratified by Eastern Cooperative Oncology Group
`
`performance status (ECOG-PS) score (0 vs 1) and randomised 1:1 to
`
`receive abiraterone acetate 1000 mg plus prednisone 5 mg twice daily by
`
`mouth or placebo plus prednisone.
`
`2.3.
`
`Efficacy outcomes
`
`The co–primary end points were radiographic progression-free survival
`
`(rPFS) and OS. OS was defined as time from randomisation to death from
`
`

`
`E U R O P E A N U R O L O G Y 6 6 ( 2 0 1 4 ) 8 1 5 – 8 2 5
`
`817
`
`any cause. The rPFS endpoint was defined as time from randomisation to
`
`Table 1 – Baseline patient characteristics
`
`radiographic progression, as previously described [15], or death. The
`
`prespecified secondary efficacy end points were time to opiate use for
`
`cancer pain, time to initiation of cytotoxic chemotherapy, time to
`
`deterioration in ECOG-PS, and time to prostate-specific antigen (PSA)
`
`progression based on Prostate Cancer Working Group 2 (PCWG2) criteria
`
`[17]. Exploratory end points included PSA response rate, defined as the
`proportion of patients achieving a PSA decline 50% according to PCWG2
`criteria [17]. Patient-reported outcomes (PROs) related to pain and
`
`functional status were prespecified in the study protocol (Supplement).
`
`2.4.
`
`Safety
`
`Clinical assessments were conducted at prespecified visits and included
`
`medical history, vital sign measurements, body weight, physical
`
`examination, review of concomitant therapy and procedures, and
`
`review of adverse events (AEs) and serious AEs.
`
`2.5.
`
`Statistical analyses
`
`All randomised patients were included in the intent-to-treat population,
`
`regardless of treatment received, and were analysed according to the
`
`randomised treatment group. All patients who received study treatment
`
`were included in the safety population [18]. Three interim analyses were
`
`planned for the OS end point at approximately 15%, 40%, and 55% OS
`
`events. The data cut-off for the IA3 was 22 May 2012, and the actual
`
`analysis was conducted at 56% OS events (434 of 773 events).
`
`Median time-to-event end points were estimated using the Kaplan-
`
`Meier product limit method, and the log-rank test was used to compare
`
`the treatment differences. The HR and associated 95% CIs were estimated
`
`by the Cox proportional hazards model [18]. A significance level of 0.04
`
`(0.0035 for IA3) was allocated for the OS end point (three interim and a
`
`final) using the O’Brien-Fleming boundaries as implemented by the Lan-
`
`DeMets a-spending function [19]. An exploratory multivariate analysis
`
`for OS using the Cox proportional hazards model, adjusting for known
`
`baseline prognostic factors, was performed. The incidence of grade 1/2
`
`and 3/4 AEs was descriptively reported for patients with treatment
`exposure of <3, 12–15, and 24 mo to provide a safety overview at
`representative time points in the disease process across short- and long-
`
`term treatment duration. The cumulative incidence of selected AEs from
`
`time to first incidence of the AE is summarised graphically.
`
`3.
`
`Results
`
`A total of 1088 patients were randomised 1:1 to study
`treatments: 546 to abiraterone plus prednisone therapy and
`542 to prednisone therapy. Patients were evenly matched
`between treatment groups, and baseline characteristics
`were consistent with asymptomatic/minimally symptom-
`atic chemotherapy-naive mCRPC (Table 1) [15]. At IA3, the
`median follow-up duration of OS for the intent-to-treat
`population was 27.1 mo. The median treatment duration at
`IA3 was 13.8 mo (range: 0.3–34.9) for abiraterone and 8.3
`mo (range: 0.1–32.4) for prednisone.
`At the time of analysis, treatment was ongoing for 23% of
`the patients in the abiraterone group and 11% of the patients
`in the prednisone group, while treatment discontinuations
`because of AEs were low across treatment groups (8% vs 6%,
`respectively) (Supplemental Fig. 1). Most patients discon-
`tinued therapy because of disease progression (57% in the
`abiraterone group and 68% in the prednisone group); the
`majority went on to receive cytotoxic chemotherapy for
`
`Characteristic
`
`Median age, yr (IQR)
`Median time from initial
`diagnosis to first dose, yr (IQR)
`Median PSA, ng/ml (IQR)
`Gleason score (8) at initial
`diagnosis, no. (%)
`Extent of disease, no. (%)
`Bone metastases
`>10
`Soft tissue or node*
`Pain at screening (BPI-SF), no. (%)
`0–1
`2–3
`BPI-SF score, mean  SD;
`median (IQR)
`Pain intensity
`
`Worst pain intensity
`
`Pain interference
`
`FACT-P total score
`Mean  SD
`Median (IQR)
`
`Abiraterone
`plus prednisone,
`n = 546
`
`Prednisone
`alone,
`n = 542
`
`71 (65–77)
`5.5 (2.7–9.7)
`
`70 (63–76)
`5.1 (2.8–9.1)
`
`42.0 (16.1–116.0)
`263 (54)
`
`37.7 (14.9–95.3)
`254 (50)
`
`452 (83)
`264 (49)
`267 (49)
`
`353 (66)
`169 (32)
`n = 539
`
`432 (80)
`253 (47)
`271 (50)
`
`336 (64)
`170 (33)
`n = 534
`
`0.8  1.1;
`0.5 (0–1.25)
`1.2  1.7;
`0 (0–2)
`0.7  1.3;
`0 (0–0.9)
`n = 527
`122.1  17.0
`124.0 (112.0–134.7)
`
`0.8  1.1;
`0.5 (0–1.25)
`1.2  1.6;
`1 (0–2)
`0.7  1.2;
`0.1 (0–1.0)
`n = 526
`122.6  17.7
`126.0 (112.0–137.0)
`
`BPI-SF = Brief Pain Inventory–Short Form; FACT-P = Functional Assessment
`of Cancer Therapy–Prostate; IQR = interquartile range (25th and 75th
`quartiles); PSA = prostate-specific antigen; SD = standard deviation.
`* Excludes visceral metastases.
`
`Table 2 – Subsequent therapy for prostate cancer
`
`Abiraterone
`plus prednisone
`(n = 546), no. (%)
`
`Prednisone
`alone (n = 542),
`no. (%)
`
`274 (50)
`
`348 (64)
`
`239 (44)
`60 (11)
`39 (7)
`38 (7)
`33 (6)
`
`304 (56)
`70 (13)
`63 (12)
`78 (14)
`28 (5)
`
`Patients with selected
`subsequent therapy
`for mCRPC*
`Docetaxel
`Cabazitaxel
`Ketoconazole
`Abirateroney
`Sipuleucel-T
`
`mCRPC = metastatic castration-resistant prostate cancer.
`Table reports cumulative incidence of subsequent therapy regardless of
`sequence after study drug discontinuation to the third interim analysis
`clinical cut-off date of 22 May 2012.
`* First patient crossover after unblinding on 7 May 2012.
`y Prior to unblinding and crossover from the prednisone arm to the
`abiraterone arm.
`
`unequivocal clinical progression, as defined per protocol.
`Subsequent therapy with docetaxel was common in the
`abiraterone group (44%) and the prednisone group (56%),
`while 7% and 14% of patients, respectively, received
`subsequent abiraterone plus prednisone treatment (Table 2).
`
`3.1.
`
`Efficacy outcomes
`
`Patients receiving abiraterone compared with prednisone
`had statistically significant
`improvement
`in rPFS
`( p < 0.0001), with a median time to disease progression
`
`

`
`818
`
`E U R O P E A N U R O L O G Y 6 6 ( 2 0 1 4 ) 8 1 5 – 8 2 5
`
`or death (per protocol definition) of 16.5 mo versus 8.2 mo,
`respectively (HR: 0.52; p < 0.0001) (Fig. 1A). This improve-
`ment was observed across all patient subgroups (Fig. 1B). The
`OS analysis favoured abiraterone therapy over prednisone
`(median: 35.3 vs 30.1 mo; HR: 0.79; p = 0.0151) but did not
`
`cross the prespecified statistical boundary with an a-level of
`0.0035 (Fig. 2). An exploratory multivariate analysis adjust-
`ing for baseline prognostic factors supported an OS benefit
`for abiraterone versus prednisone (HR: 0.74; p = 0.0017)
`(Table 3). Baseline serum PSA,
`lactate dehydrogenase,
`
`(A)
`
`value:
`
`Months
`
`(B)
`
`Favours
`
`Favours
`
`Fig. 1 – Co–primary end point: (A,B) radiographic progression-free survival assessed by investigator review at prespecified interim analysis. (B) The size of
`the circle reflects the number of patients affected. For hazard ratio (HR) <1, the result favours abiraterone.
`AA = abiraterone; ALK-P = alkaline phosphatase; BPI = Brief Pain Inventory; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group;
`LDH = lactate dehydrogenase; N.A. = North America; P = prednisone; PSA = prostate-specific antigen.
`
`[(Fig._1)TD$FIG]
`

`
`(A)
`
`(B)
`
`E U R O P E A N U R O L O G Y 6 6 ( 2 0 1 4 ) 8 1 5 – 8 2 5
`
`819
`
`value*:
`
`Favours
`
`Favours
`
`Fig. 2 – Co–primary end point: (A,B) overall survival. Prespecified significance level by the O’Brien-Fleming boundary = 0.0035. (B) The size of circle reflects
`the number of patients affected. For hazard ratio (HR) <1, the result favours abiraterone.
`AA = abiraterone; ALK-P = alkaline phosphatase; BPI = Brief Pain Inventory; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group;
`LDH = lactate dehydrogenase; N.A. = North America; NE = not estimable; P = prednisone; PSA = prostate-specific antigen.
`
`alkaline phosphatase, haemoglobin, bone metastasis, and age
`were significant prognostic factors ( p < 0.01) (Table 3).
`All secondary end points favoured abiraterone versus
`prednisone (Fig. 3). Abiraterone delayed the time to opiate
`
`use for cancer-related pain (HR: 0.71; p = 0.0002) and time to
`initiation of chemotherapy (HR: 0.61; p < 0.0001). Abirater-
`one also delayed the time to deterioration in ECOG-PS (HR:
`0.83; p = 0.005) and PSA progression (HR: 0.50; p < 0.0001).
`
`[(Fig._2)TD$FIG]
`

`
`820
`
`E U R O P E A N U R O L O G Y 6 6 ( 2 0 1 4 ) 8 1 5 – 8 2 5
`
`Table 3 – Exploratory multivariate analysis of overall survival
`
`3.2.
`
`Patient-reported outcomes
`
`Parameter*
`
`Treatment (abiraterone plus prednisone
`vs prednisone alone)
`ECOG score (1 vs 0)
`Log (baseline serum PSA, ng/ml)
`Log (baseline lactate dehydrogenase, IU/l)
`Log (baseline alkaline phosphatase, IU/l)
`Baseline haemoglobin, g/dl
`Bone metastasis only at baseline, yes vs no
`Age
`
`Hazard
`ratio (95% CI)
`
`p value
`
`0.74 (0.61–0.89)
`
`0.002
`
`0.2
`1.17 (0.94–1.45)
`1.18 (1.10–1.27) <0.0001
`3.07 (2.11–4.48) <0.0001
`1.33 (1.14–1.56)
`0.0003
`0.92 (0.85–0.99)
`0.02
`0.69 (0.57–0.85)
`0.0003
`1.02 (1.01–1.03)
`0.0006
`
`CI = confidence interval; ECOG = Eastern Cooperative Oncology Group;
`PSA = prostate-specific antigen.
`Patients who are not deceased at time of analysis are censored on the last
`date they were known to be alive or lost to follow-up.
`* Post hoc sensitivity analysis. Model dependent variable is overall survival,
`expressed as days from date of randomisation to death from any cause.
`
`The PSA response rate (50%) was more than doubled with
`abiraterone (68% [374 of 546]) compared with prednisone
`(29% [156 of 542]) (Fig. 4).
`
`The baseline pain scores and functional status scores
`(see Supplement
`for definitions) were well balanced
`between study groups (Table 1). The compliance rates
`across treatment groups for completion of the Brief Pain
`Inventory–Short Form and Functional Assessment of Cancer
`Therapy–Prostate (FACT-P) questionnaires were >95% each;
`compliance was defined as the number of completed
`questionnaires over the total expected. Following treatment,
`PRO scores showed a consistent pattern of delays in pain
`progression and in degradation of subscales of functional
`status for patients treated with abiraterone versus predni-
`sone (Table 4). Patients receiving abiraterone had statistically
`significant improvement in pain interference ( p = 0.005)
`versus prednisone, although the improvement in mean pain
`intensity ( p = 0.061) was not significant (Table 4).
`Using the prespecified 30% change from baseline in
`pain intensity as the minimal important difference, the
`worst pain intensity was not significantly different between
`treatment groups ( p = 0.113) (Table 4). Abiraterone treat-
`ment did delay degradation in FACT-P total scores
`
`(A)
`
`(B)
`
`value:
`
`value:
`
`(C)
`
`(D)
`
`value:
`
`value:
`
`Fig. 3 – Secondary end points: (A) time to opiate use for cancer-related pain; (B) time to initiation of chemotherapy; (C) time to deterioration in the Eastern
`Cooperative Oncology Group (ECOG) score; (D) time to prostate-specific antigen (PSA) progression.
`AA = abiraterone; CI = confidence interval; HR = hazard ratio; NR = not reached; P = prednisone.
`
`[(Fig._3)TD$FIG]
`

`
`E U R O P E A N U R O L O G Y 6 6 ( 2 0 1 4 ) 8 1 5 – 8 2 5
`
`821
`
`Fig. 4 – Maximal prostate-specific antigen (PSA) decline from baseline. A negative percentage indicates a decline in PSA. A positive percentage indicates
`that the patient never has a decline in PSA.
`
`Table 4 – Patient-reported outcomes
`
`PRO end points
`
`Median time to pain progression, mo
`Mean pain intensityz
`Pain interference###
`Worst pain intensityz (prespecified analysis)
`Median time to functional status degradation, mo
`FACT-P total scorejj
`FACT general scoreô
`Prostate Cancer Subscale
`Physical well-being
`Functional well-being
`Trial outcome index**
`Social/family well-being
`Emotional well-being
`
`Abiraterone plus prednisone,
`n = 546
`
`Prednisone alone,
`n = 542
`
`Hazard ratio*
`(95% CI)
`
`p valuey
`
`26.7
`10.3
`25.8
`
`12.7
`16.6
`11.1
`14.8
`13.3
`13.9
`18.4
`22.5
`
`18.4
`7.4
`20.3
`
`8.3
`11.1
`5.8
`11.1
`8.4
`9.3
`16.6
`14.2
`
`0.83 (0.68–1.01)
`0.80 (0.68–0.93)
`0.85 (0.69–1.04)
`
`0.79 (0.67–0.93)
`0.76 (0.64–0.91)
`0.72 (0.61–0.84)
`0.76 (0.64–0.91)
`0.77 (0.65–0.91)
`0.77 (0.65–0.91)
`0.95 (0.78–1.15)
`0.73 (0.61–0.89)
`
`0.06
`0.005
`0.1
`
`0.005
`0.002
`<0.0001
`0.002
`0.002
`0.002
`0.6
`0.002
`
`BPI-SF = Brief Pain Inventory–Short Form; CI = confidence interval; FACT = Functional Assessment of Cancer Therapy; FACT-P = Functional Assessment of Cancer
`Therapy–Prostate; PRO = patient-reported outcomes.
`* Obtained from stratified proportional hazards model. Hazard ratio <1 favours abiraterone plus prednisone.
`y Obtained from log-rank test stratified by Eastern Cooperative Oncology Group performance status (0 or 1).
`z Progression: 30% increase from baseline in BPI-SF score without decreased analgesic usage score, at two consecutive visits.
`### Pain interference progression: an increase at any visit in the baseline BPI-SF pain interference score of one-half the baseline standard deviation of BPI-SF.
`jj Total score consists of FACT general and Prostate Cancer Subscale scores.
`ô FACT general score consists of physical well-being, social/family well-being, emotional well-being, and functional well-being subscales.
`** Trial outcome index consists of physical well-being, functional well-being, and Prostate Cancer Subscale.
`
`( p = 0.005)
`subscale scores
`and in the PCa-specific
`( p < 0.0001) versus prednisone (Table 4). All other FACT-P
`subscales also favoured abiraterone versus prednisone,
`except the social/family well-being subscale ( p = 0.577).
`
`3.3.
`
`Safety
`
`AEs are summarised in Table 5. The most frequently
`reported AEs (15% of patients in either group) were
`similar to those reported previously (Table 5) [15]. The most
`frequently reported grade 3/4 AEs in the abiraterone or
`prednisone treatment groups (reported in 3% of patients
`in either group) were alanine aminotransferase (ALT)
`increased (6% [30 of 542] vs 1% [4 of 540]), hypertension
`(4% [23 of 542] vs 3% [17 of 540]), back pain (3% [15 of 542]
`vs 4% [21 of 542]), hyperglycaemia (3% [14 of 542] vs 2% [11
`of 540]), hypokalaemia (3% [14 of 542] vs 2% [10 of 542]),
`aspartate aminotransferase (AST) increased (3% [17 of 542]
`vs 1% [5 of 540]), and dyspnoea (3% [14 of 542] vs 1% [5 of
`540]), respectively.
`AEs leading to dose modifications or interruption of
`treatment occurred in 21% of patients receiving abiraterone
`
`(112 of 542) and in 12% of patients in the prednisone group
`(65 of 540) and included ALT increased, AST increased,
`hypertension, and vomiting. AEs leading to death occurred
`in 4% of patients in the abiraterone group (21 of 542) and 3%
`of patients in the prednisone group (16 of 540). Drug-
`related treatment-emergent AEs leading to death occurred
`in 1% of patients in each treatment group (6 patients each).
`AEs of special
`interest
`included events related to
`mineralocorticoid excess (hypertension, hypokalaemia,
`fluid retention) based on the known mechanism of action
`of abiraterone. Grade 3 or 4 mineralocorticoid-related AEs
`and increases in ALT and AST were more common with
`abiraterone (Table 5). The grade 3 or 4 AEs of increased ALT
`and AST remained higher in the abiraterone group (6% [30 of
`542] and 3% [17 of 542]) versus the prednisone group (1% [4
`of 540] and 1% [5 of 540]), respectively. Grade 3 or 4 cardiac
`disorder AEs in the abiraterone versus the prednisone group
`were rare: arrhythmias (4% [21 of 542] vs 2% [11 of 540]),
`ischaemic heart disease (2% [11 of 542] vs 1% [8 of 540]),
`cardiac failure (1% [6 of 542] vs 0), and cardiac disorders of
`other causes (<1% each), respectively. Cardiac disorders
`that led to treatment discontinuation were also extremely
`
`[(Fig._4)TD$FIG]
`

`
`822
`
`E U R O P E A N U R O L O G Y 6 6 ( 2 0 1 4 ) 8 1 5 – 8 2 5
`
`Table 5 – Safety overview and adverse events of special interest
`
`Abiraterone plus prednisone
`(n = 542), no. (%)
`
`Prednisone alone
`(n = 540), no. (%)
`
`AEs (grade 14)
`Grade 3/4 AE
`Any serious AE
`AE leading to treatment discontinuation
`AE leading to death
`
`538 (99)
`267 (49)
`188 (35)
`58 (11)
`21 (4)
`
`524 (97)
`235 (44)
`146 (27)
`53 (10)
`16 (3)
`
`Common AEs (15% patients in either group)
`
`Grade 14, no. (%)
`
`Grade 14, no. (%)
`
`Fatigue
`Back pain
`Arthralgia
`Peripheral oedema
`Nausea
`Constipation
`Hot flush
`Diarrhoea
`Hypertension
`Bone pain
`Cough
`Hypokalaemia
`Pain in extremity
`Musculoskeletal pain
`Insomnia
`Muscle spasm
`
`215 (40)
`180 (33)
`159 (29)
`141 (26)
`130 (24)
`128 (24)
`123 (23)
`127 (23)
`118 (22)
`113 (21)
`98 (18)
`93 (17)
`93 (17)
`88 (16)
`79 (15)
`77 (14)
`
`187 (35)
`179 (33)
`132 (24)
`113 (21)
`124 (23)
`110 (20)
`99 (18)
`98 (18)
`73 (14)
`103 (19)
`74 (14)
`69 (13)
`87 (16)
`81 (15)
`62 (12)
`111 (21)
`
`AEs of special interest
`
`Grade 14, no. (%)
`
`Grades 3/4, no. (%)
`
`Grade 14, no. (%)
`
`Grades 3/4, no. (%)
`
`Fatigue
`Fluid retention
`Hypertension
`Cardiac disorders
`Hypokalaemia
`ALT increased
`AST increased
`Hyperglycaemia
`Weight gain
`
`215 (40)
`159 (29)
`118 (22)
`110 (20)
`93 (17)
`65 (12)
`60 (11)
`47 (9)
`28 (5)
`
`13 (2)
`5 (1)
`23 (4)
`36 (7)
`14 (3)
`30 (6)
`17 (3)
`14 (3)
`0
`
`187 (35)
`130 (24)
`73 (14)
`92 (17)
`69 (13)
`27 (5)
`26 (5)
`43 (8)
`39 (7)
`
`10 (2)
`9 (2)
`17 (3)
`19 (4)
`10 (2)
`4 (1)
`5 (1)
`11 (2)
`0
`
`AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase.
`
`rare and were reported in <1% of patients in each treatment
`group. In a post hoc analysis, the incidence of selected grade
`3 or 4 AEs was low, despite longer abiraterone treatment
`exposure (Supplemental Fig. 2). The cumulative incidence
`of selected AEs (all grades) from the time of first event was
`similar across treatment groups (Supplemental Fig. 3).
`
`4.
`
`Discussion
`
`We present the updated efficacy and safety outcomes from
`the prespecified IA3, with longer treatment exposure and a
`greater number of death events—434 compared with 333 in
`the previous analysis [15]. With a longer follow-up of
`27.1 mo, the current results confirm the clinical benefits of
`abiraterone versus prednisone in chemotherapy-naive
`patients with mCRPC, including significantly delayed time
`to disease progression (16.5 mo vs 8.2 mo; HR: 0.52;
`p < 0.0001). Abiraterone therapy improved OS compared
`with prednisone (median: 35.3 mo vs 30.1 mo; HR: 0.79;
`p = 0.0151), but this result did not cross the prespecified
`efficacy boundary for statistical significance, as defined
`by the O’Brian-Fleming boundary implemented by the
`Lan-DeMets a-spending function.
`This study also used two primary end points and several
`clinically relevant secondary end points to establish efficacy
`
`and clinical benefit. Previous findings at IA2 of this study
`showed that rPFS, when assessed by investigator review,
`was consistently and robustly associated with OS, with a
`Spearman correlation coefficient of 0.72 between the two
`end points [15,20]. All secondary end points (time to opiate
`use for cancer-related pain, time to cytotoxic chemothera-
`py, time to ECOG-PS deterioration by at least one grade,
`time to PSA progression) remained consistent with the
`results of previous analyses [15] and demonstrated
`statistically significant differences in favour of treatment
`with abiraterone compared with prednisone.
`Additionally,
`this study incorporated and reported
`prespecified, validated PRO measures to show that abir-
`aterone treatment delayed pain progression and deteriora-
`tion of
`functional status compared with prednisone,
`consistent with our previous IA2 report [21]. Along with
`previous explorations of PROs in patients with mCRPC
`following chemotherapy [22–24], the current data further
`confirm the value of addressing the concerns of patients and
`clinicians related to improvements in how the patient feels
`and functions during treatment.
`Unmet needs for chemotherapy-naive patients with
`progressive mCRPC are low toxicity and effective treat-
`ments that can prolong life, delay disease progression, and
`maintain quality of life [25]. Second-line antiandrogens,
`
`

`
`E U R O P E A N U R O L O G Y 6 6 ( 2 0 1 4 ) 8 1 5 – 8 2 5
`
`823
`
`nonspecific adrenal androgen inhibitors, and oestrogen-
`based therapies are associated with PSA responses in some
`patients, but the effects of these agents on survival are
`unknown [25–27]. Sipuleucel-T, an immunotherapeutic
`drug, has demonstrated significant survival benefit over
`placebo for patients with mCRPC (median OS: 25.8 mo vs
`21.7 mo; p = 0.03)
`[28], with no impact on disease
`progression (median: 3.7 mo vs 3.6 mo; p = 0.63) or post-
`therapy changes in PSA. Enzalutamide is approved in the
`United States and the European Union based on survival
`benefits in patients with mCRPC following chemotherapy
`[29], and positive results for chemotherapy-naive mCRPC
`were recently announced [30]. Radium 223 chloride is
`approved in the United States and Europe for patients with
`symptomatic bone mCRPC without visceral metastasis [31].
`The most common subsequent therapy for patients who
`terminated the study was docetaxel in both study groups
`(44% for abiraterone; 56% for prednisone). As the data cut-off
`date for the current analysis (22 May 2012) was in proximity
`to the date of unblinding of the study, as recommended by the
`independent data-monitoring committee (7 May 2012), only
`three patients had crossed over from the prednisone group to
`receive abiraterone. Hence, the unblinding of the study is
`unlikely to have had a significant impact on the study results
`presented in this paper.
`The safety findings of the updated results with longer
`follow-up are similar to those of the previous report [15],
`with mostly grade 1 or 2 AEs. Among AEs of special interest,
`only increased ALT or AST remained higher
`in the
`abiraterone group than in the prednisone group, similar
`to the previous observation [15]. Post hoc analyses of long-
`term safety did not reveal any new safety findings in
`treatment exposure with
`patients with 24 mo of
`abiraterone or with prednisone. Despite the limitation of
`a post hoc analysis, these results are particularly reassuring
`for clinicians who may be concerned about long-term side-
`effects of prolonged prednisone exposure.
`
`5.
`
`Conclusions
`
`In patients with asymptomatic and mildly symptomatic
`mCRPC without prior chemotherapy,
`treatment with
`abiraterone plus prednisone significantly delayed disease
`progression, time to opiate use, and initiation of chemo-
`therapy, and it was associated with an increase in OS.
`Abiraterone also delayed functional decline and progression
`of pain interference compared with prednisone alone. No
`new safety signals were observed with 24 mo of treatment
`with abiraterone or with prednisone. With the follow-up
`duratio