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Review – Prostate Cancer

Achievements and Perspectives in Prostate Cancer Phase 3 Trials from Genitourinary Research Groups in Europe: Introducing the Prostate Cancer Consortium in Europe

By: Karim Fizazi a lowast , Per-Anders Abrahamsson b , Goran Ahlgren b , Joaquim Bellmunt c , Daniel Castellano d , Stephane Culine e , Ronald de Wit f , Silke Gillessen g , Juergen E. Gschwend h , Freddie Hamdy i , Nicholas James j , Raymond McDermott k , Kurt Miller l , Thomas Wiegel m , Manfred Wirth n and Bertrand Tombal o

European Urology, Volume 67 Issue 5, May 2015, Pages 904-912

Published online: 01 May 2015

Keywords: Phase 3 trials, Clinical research, European consortium

Abstract Full Text Full Text PDF (286 KB) Patient Summary

Abstract

Context

Phase 3 trials have made major contributions to advances in prostate cancer (PCa). However, funding limitations and excess bureaucracy are now making it difficult to conduct trials.

Objective

To describe the collaborative groups in Europe and their academic phase 3 PCa trials.

Evidence acquisition

Leaders of collaborative groups from Scandinavia, the European Organisation for Research and Treatment of Cancer (EORTC), France, Spain, the United Kingdom, Germany, Switzerland, The Netherlands, and Ireland were asked to provide information.

Evidence synthesis

Approximately 40 academic European phase 3 trials focussing on PCa have been completed, and about 10 are accruing patients. Cross-border trials have been successfully conducted led by EORTC (11), Scandinavian Prostate Cancer Group (9), European Association of Urology (1), Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficiency (STAMPEDE) (1), and the French Genito-Urinary Tumor Group (1). Among these studies were practise-changing trials showing the superiority of prostatectomy over watchful waiting in patients <65 yr of age, the benefits of combining androgen-deprivation therapy (ADT) with radiation therapy (RXT) in high-risk localised disease, the superiority of long-term versus short-term ADT, the benefit of RXT in men treated with ADT, and the role of adjuvant RXT. To bridge the numbers gap for phase 3 studies, the Prostate Cancer Consortium in Europe (PEACE) is a recently established initiative that aims to favour cross-border networks of investigators. PEACE 1 is testing the addition of abiraterone and that of RXT directed at the primary cancer in patients with de novo metastatic PCa treated with ADT. PEACE 2 is testing the addition of cabazitaxel and that of pelvic irradiation in patients with at least two criteria for high-risk localised PCa.

Conclusions

European academic phase 3 trials have contributed to establishing the current standard treatment of PCa. The PEACE consortium was recently tasked with the goal of addressing unanswered questions and specific biology-related issues more efficiently.

Patient summary

The Prostate Cancer Consortium in Europe was established to conduct comparative trials aiming at assessing new treatments for prostate cancer patients.

Take Home Message

European academic phase 3 trials have contributed to establishing the current standard treatment of prostate cancer. The Prostate Cancer Consortium in Europe recently set the goal of addressing unanswered questions and specific biology-related issues more efficiently.

Keywords: Phase 3 trials, Clinical research, European consortium.

1. Introduction

Prostate cancer (PCa) is the second most common cancer in men, and numbers continue to rise. In 2012, there were 417 000 new cases of PCa in Europe [1] compared with 370 700 in 2008 [2] , although there is considerable variation in trends. Data from GLOBOCAN 2008, compiled from estimates from the International Agency for Research on Cancer, showed changes in incidence ranging from an annual decrease of 0.2% in Finland to annual increases of 2.3%, 5.4%, 7.7%, and 16.4% in Sweden, France, Poland, and Lithuania, respectively [2] . This heterogeneity is thought to reflect variations in health care services, notably the availability of prostate-specific antigen (PSA) testing [3] . PSA testing is also resulting in diagnosis at an earlier stage of disease, with fewer men having metastatic disease at diagnosis. Recent follow-up data from the European Randomised Study for Screening of Prostate Cancer show that 2.7% of men with PCa diagnosed following screening had M1 disease and/or a PSA >100, compared with 7% of those diagnosed with PCa who had not been offered screening [4] . PCa mortality is falling in most European countries [2] . During the last two decades, phase 3 clinical trials have played an important part in the improvements in PCa treatment, which, together with earlier diagnosis, are likely to have contributed to the general trend in declining mortality in Europe.

Among these studies were important phase 3 trials conducted in men with high-risk localised disease showing the benefits of combining androgen-deprivation therapy (ADT) with radiation therapy (RXT) [5] , the superiority of long-term versus short-term ADT when combined with RXT [6] , the benefit of RXT in men treated with ADT [7] , and the role of adjuvant RXT after radical prostatectomy (RP)[8] and [9]. Together, these have led to major changes in clinical practice. Other key trials have included demonstration of the superiority of RP over watchful waiting in patients <65 yr of age with PCa [10] .

Even with relatively small numbers of patients, such phase 3 trials have been powered to answer big questions, thanks to the large predicted gains of one treatment option over another. As the expected advantages of newer treatment options inevitably become smaller, much larger patient numbers (ie, 600–1500 patients) will be needed for future phase 3 trials aimed at further improving the prognosis for men at all stages of PCa. The growing interest in personalised medicine, based on genotypic information and biomarkers, may reduce the future need for large phase 3 trials. However, that situation has not yet been reached for PCa and may not occur in the short to medium term, especially in producing the necessary overall survival (OS) and progression-free survival (PFS) data that currently drive clinical practice.

By grouping together into national organisations, European specialists in genitourinary (GU) cancers have gone some way to addressing the numbers gap in phase 3 clinical trials and are making significant contributions to research and best practice in GU cancer treatment. However, few of these national GU cancer groups focus solely on PCa, and most must use their membership and funding to address the needs of patients with other types of GU cancer. Pan-European organisations such as the European Organisation for Research and Treatment of Cancer (EORTC) are also playing an important role in advancing the care of patients with cancers, but they have an even broader remit than national GU cancer groups and organise clinical trials in all cancers. For these reasons, in 2012 we started to investigate the potential for a pan-European research group, open to all PCa specialists practising in the European Union (EU)-27 countries, and to those in non-EU countries, specifically to address the growing need for phase 3 clinical trials in PCa.

The objectives of this paper are briefly to describe the role of the GU groups currently involved in PCa research in Europe, to summarise the results of phase 3 trials carried out by these groups, and to discuss the potential of the new Prostate Cancer Consortium in Europe (PEACE) for conducting large rapid pan-European studies and addressing specific biology-related issues in the field of PCa research.

2. Evidence acquisition

In June 2012, we invited the European urology and oncology groups that we knew to be undertaking PCa research to participate in this review. We apologise to any groups of which we were unaware for not including them. Participating organisations were asked to summarise their objectives and achievements to date, and to provide information about their past and ongoing phase 3 trials related to treatment of all stages of PCa.

3. Evidence synthesis

3.1. Regional prostate cancer collaborative groups in Europe

Responses were received from 10 pan-European and national groups: the EORTC Genito-Urinary Cancers Group (EORTC-GUCG), the European Association of Urology (EAU), the Scandinavian Prostate Cancer Group (SPCG), the French Genito-Urinary Tumor Group (GETUG), the British GU Group (National Cancer Research Institute [NCRI] Prostate Cancer Clinical Studies Group), the Spanish Oncology Genito-Urinary Group (SOGUG), the GU Project Group of the Swiss Group for Clinical Cancer Research (SAKK-GU), the Dutch Uro-Oncology Study (DUOS) Group, the Irish Clinical Oncology Research Group, and the Arbeitsgemeinschaft Radiologische Onkologie (ARO) and Arbeitsgemeinschaft Urologische Onkologie (AUO) of the German Cancer Society. Their responses are summarised below and inTable 1 and Table 2.

Table 1 Past phase 3 trials for patients with prostate cancer

Trial name PCa stage No. of patients Main results Reference
EORTC studies
 30761 Locally advanced 89 DES and CPA equivalent; DES has more cardiovascular toxicity De Voogt et al. [15]
  Metastatic 118    
 30895 Metastatic 279 No benefit with CAB with CPA or DES over castration alone Robinson et al. [16]
 30853 Metastatic 327 MAB with flutamide increases OS over castration alone Denis et al. [17]
 30843 Metastatic 367 MAB with CPA does not increase OS De Voogt et al. [18]
 30892 Metastatic 310 No difference between flutamide and CPA monotherapy Schroder et al. [19]
 30893 Metastatic 189 Mitomycin does not increase efficacy of castration and is more toxic Fossa et al. [20]
 30891 Locally-advanced unfit for local treatment 493 Immediate ADT not better than delayed ADT in unfit patients Studer et al. [21] and [22]
 30846 pN+ with abandoned RP 234 Immediate ADT not better than delayed ADT Schroder et al. [23]
 22863 Locally advanced receiving EBRT 415 3 yr ADT better than no ADT, in combination with RXT Bolla et al. [5]
 22961 Locally advanced receiving EBRT 970 3 yr better than 6 mo ADT when combined with RXT Bolla et al. [6]
 22911 pT3a–b or R1 after RP 1005 Adjuvant RXT improves PFS Bolla et al. [9]
SPCG studies
 SPCG 1 T1–4, Nx, M1, G2–3 197 No difference estramustine vs DES Hedlund et al. [24]
 SPCG 2 T0–4, Nx, M1, G1–2 294 No benefit of adding CPA to orchidectomy Jørgensen et al. [25]
 SPCG 4 T1–2, N0, WHO I–II 693 Survival benefit of RP over watchful waiting in men <65 yr of age Bill-Axelson et al. [10]
 SPCG 5 T1–4, Nx, M1 915 Parenteral Estradurin equal to TAB Hedlund et al. [26]
 SPCG 6 T1–3, Nx, M0 1218 (part of the Early Prostate Cancer-programme) Bicalutamide prolongs PFS and OS in locally advanced disease Iversen et al. [27]
 SPCG 7 T1–3, N0, M0 880 RXT and hormones improve survival vs hormones alone Widmark et al. [7]
EAU studies
 ZEUS Nonmetastatic PCa at high-risk for relapse 1433 Zoledronic acid does not prevent the onset of bone metastases Wirth et al. [28]
GETUG studies
 GETUG 01 Localised 444 Pelvic node irradiation does not increase PFS in moderate-risk PCa Pommier et al. [29]
 GETUG 06 Intermediate risk localised 306 RXT 80 Gy (vs 70 Gy) provides a better 5-yr biochemical outcome Beckendorf et al. [30]
 GETUG 12 High risk localised 413 Neoadjuvant docetaxel/estramustine with ADT-RXT (vs ADT-RXT alone) improves PSA response

PFS data pending
Fizazi et al. [31]
 GETUG-AFU 14 Intermediate risk localised 378 No benefit of adding 6 mo ADT to RXT 80 Gy at interim analysis (6 mo after last patient inclusion) Dubray et al. [32]
 GETUG-AFU 15 Newly diagnosed metastatic 385 Docetaxel with ADT (vs ADT alone) improves PFS but not OS Gravis et al. [33]
NCRI Prostate Cancer Clinical Studies Group studies
 MRC RT01 trial Newly diagnosed locally advanced PCa 843 Escalated-dose RXT significantly improved bPFS with also a trend for better cPFS (p = 0.064) vs standard-dose conformal RXT Dearnaley et al. [34]
 MRC PR04 Nonmetastatic PCa after primary therapy 508 No benefit of oral clodronate for bone metastases–free survival or OS Mason et al. [35]
 MRC PR05 Metastatic PCa on hormone therapy 311 Better OS in the clodronate group reported in a long-term subgroup analysis Dearnaley et al. [36]
 MRC PR07 Newly diagnosed high-risk locally advanced PCa 1205 The addition of RXT to ADT improved overall survival at 7 yr vs ADT alone Warde et al. [14]
 STAMPEDE Newly diagnosed metastatic or high-risk locally advanced PCa 875 (in this comparison) No advantage for hormone therapy plus celecoxib over hormone therapy alone James et al. [37]
 TRAPEZE CRPC metastatic to bone treated with docetaxel 757 Sr89 delayed cPFS zoledronic acid increased SRE-free interval James et al. [38]
ARO/AUO of the German Cancer Society studies
 ARO 96-02/AUO AP 09/95 pT3 and undetectable PSA post RP 307 Adjuvant RXT improves bPFS Bottke et al. [39] ; Wiegel et al. [40]
 German Intermittent ADT study AUO AP 17/95 N+ or M1 335 No significant difference between intermittent and continuous ADT Miller et al. [41]
DUOS group
 NePro CRPC with bone metastases 592 No difference docetaxel and risedronate vs docetaxel Meulenbeld et al. [42]

ADT = androgen-deprivation therapy; ARO = Arbeitsgemeinschaft Radiologische Onkologie; AUO = Arbeitsgemeinschaft Urologische Onkologie; bPFS = biochemical progression-free survival; CAB = combined androgen blockade; CPA = cyproterone acetate; cPFS = clinical progression-free survival; CRPC = castration-resistance prostate cancer; DES = diethylstilbestrol; DUOS = Dutch Uro-Oncology Study; EAU = European Association of Urology; EBRT = external-beam radiation therapy; EORTC = European Organisation for Research and Treatment of Cancer; GETUG = (French) Genito Urinary Tumor Group; MAB = maximal androgen blockade; NCRI = National Cancer Research Institute; OS = overall survival; PCa = prostate cancer; PFS = progression-free survival; RP = radical prostatectomy; RXT = radiation therapy; SPCG = Scandinavian Prostate Cancer Group; TAB = total androgen blockade.

Table 2 Ongoing or planned phase 3 trials for patients with prostate cancer

Trial name (PI) PCa stage Planned no. of patients Question addressed by the trial Status (planned or ongoing) Clinicaltrials.gov no.
EORTC studies
 EORTC 1333 (PEACE 3) Metastatic CRPC 560 PFS enzalutamide with and without radium-223 Initialisation EudraCT 2014-001787-36
 14XX-EORTC-ROG High-risk localised ±1400 EBRT and degarelix vs LHRH agonist Planned  
SPCG studies *
 SPCG 11 T1–3, N0–1, M0 250 of 1300 (part of the ZEUS study) Prolonged time to metastasis by zoledronic acid Follow-up  
 SPCG 12 pT2–3b,N0–1, M0 459 Adjuvant docetaxel vs surveillance after RP Follow-up NCT00376792
 SPCG 13 T2–3, N0–1, M0 360 Adjuvant docetaxel vs surveillance after RXT and HT Follow-up NCT00653848
 SPCG 14 T1–3, Nx–1, M0 160/350 Bicalutamide with and without docetaxel in rising PSA Recruiting  
 SPCG 15 T3, N0–1, M0 400 RP vs RXT with adjuvant treatments Planned  
GETUG studies
 GETUG-AFU 16

 (Christian Carrie)
Rising PSA after RP 743 RXT vs RXT and ADT

Results pending
Accrual completed NCT00423475
 GETUG-AFU 17

 (Pierre Richaud)
pT3 with positive margins 718 Adjuvant or delayed RXT combined with ADT (6 mo) Accrual ongoing NCT00667069
 GETUG-AFU 18

 (Christophe Hennequin)
High-risk localised 500 RXT (70 Gy vs 80 Gy) in combination with ADT (3 yr) Fully accrued NCT00967863
 AFU-GETUG 20

 (François Rozet)
High-risk post RP (pT3b and/or Gleason score >7) 700 Adjuvant ADT vs surveillance Accrual ongoing NCT01442246
NRCI Prostate Cancer Clinical Studies Group studies
 STAMPEDE

 (Nick James)
Newly diagnosed metastatic or high-risk locally advanced PCa Trial is programmatic with new arms added as original arms complete. Each arm powered as individual trial. Does upfront use of therapy at commencement of ADT improve OS: Docetaxel

Zoledronic acid

Abiraterone

RXT to prostate
Ongoing ISRCTN78818544
 RADICALS

 (Chris Parker)
Post RP 1000-2000 To assess need for and timing of RXT and ADT after RP Ongoing ISRCTN 40814031
 ProtecT

 (Freddie Hamdy, Jenny Donovan, David Neal)
T1–T2 localised PCa, PSA <20 ng/ml 1500 Active surveillance vs RP vs RXT plus ADT Accrual completed NCT00632983

HTA NIHR 96/20/99
ARO/AUO of the German Cancer Society studies
 PREFERE

 (Michael Stöckle and Thomas Wiegel)
Localised ≤cT2a, NX/N0 M0

Gleason score ≤7a

PSA <10 ng/ml
7600 Active surveillance vs RP vs EBRT vs permanent seed implantation Ongoing DRKS00004405
 ART-2

 (Thomas Wiegel)
pN+

(micrometastases or 1–2 positive LNs)
298 Wait and see vs adjuvant RT to prostate bed and pelvic LN Ongoing DRKS00004733
 AUO AP 55/09

 SEAL (Axel Heidenreich)
Intermediate/high risk 500 Limited vs extended lymphadenectomy Ongoing  
 AUO AP 71/12 Qualifying for active surveillance 240 Pomegranate for 2 yr vs no pomegranate Planned  
SAKK-GU group studies
 SAKK 09/10

 (Pirus Ghadjar)
Biochemical relapse after RP without macroscopic disease 350 RXT 64 Gy vs 70 Gy Accrual completed NCT01272050
 SAKK 08/11

 (Richard Cathomas)
Metastatic CRPS, nonprogressive after docetaxel 192 Maintenance therapy with orteronel vs placebo Ongoing NCT01707966
 SAKK 96/12

 (Roger von Moos)
Metastatic CRPC with bone metastases Total 1380 (700 with PCa) Denosumab 120 mg every 4 wk vs every 12 wk Planned NCT02051218
SOGUG studies
 QRT-SOGUG High-risk localised PCa 150 RXT 74 Gy and ADT vs RXT 74 Gy and ADT and doxorubicin Accrual completed EUDRACT 2008-003554-14
 SOG-ABI-2013-03 ABIDO Metastatic CRPC, asymptomatic disease 120 Abiraterone 1000 mg/d followed by docetaxel vs placebo Ongoing NCT02036060

* Recruited or planned number of patients.

ADT = androgen-deprivation therapy; AFU = French Association of Urologists; ARO = Arbeitsgemeinschaft Radiologische Onkologie; AUO = Arbeitsgemeinschaft Urologische Onkologie; CRPC = castration-resistant prostate cancer; EBRT = external-beam radiation therapy; EORTC = European Organisation for Research and Treatment of Cancer; GETUG = French Genito-Urinary Tumor Group; HT = hormone therapy; LHRH = luteinising hormone-releasing hormone; LN = lymph node; NRCI = National Cancer Research Institute; OS = overall survival; PCa = prostate cancer; PEACE = Prostate Cancer Consortium in Europe; PI = principal investigator; PSA = prostate-specific antigen; ROG = Radiation Oncology Group; RP = radical prostatectomy; RXT = radiation therapy; SAKK-GU = Genitourinary Project Group of the Swiss Group for Clinical Cancer Research; SOGUG = Spanish Oncology Genito-Urinary Group; SPCG = Scandinavian Prostate Cancer Group.

The EORTC was created in 1962. Two EORTC groups are involved in GU studies, the GUCG and the Radiation Oncology Group (ROG). Founded 35 yr ago, the former GU Group, in collaboration with the ROG, conducted a total of 99 clinical trials. From the very beginning, the GU Group adopted a multidisciplinary approach, with collaboration between urologists, medical oncologists, radiation oncologists, pathologists, and biostatisticians. Like many organisations, the GU Group was confronted with a more complex regulatory environment and the economic downturn. This led to a major strategic reorganisation of the group in 2010 and the creation of the GUCG. Although GUCG still conducts large phase 3 trials, it also now focusses on studies comprising translational research, molecular and imaging screening platforms for individualised therapy, health-economic end points, and patient survivorship issues.

The EAU was founded in 1973. It has rarely been involved directly in organising phase 3 trials for PCa, with the exception of the Zotarolimus-eluting Endeavor Sprint Stent in Uncertain DES [diethylstilbestrol] Candidates (ZEUS) trial, which tested the role of early zoledronic acid to prevent the onset of bone metastases.

The SPCG was founded in 1981 by Scandinavian urologists as a collaborative group within the Scandinavian Association of Urology. On the SPCG board are two urologists from each Scandinavian country, and it is proposed that one oncologist from each country should also join. Principal investigators from each SPCG study are affiliated to the board. The group has sponsored 14 phase 3 studies over the past 30 yr, resulting in >60 original articles.

The French GETUG was launched in 1994 with the objective of implementing phase 3 studies to deal with strategic issues in the management of patients with prostate, testis, renal, and bladder cancer. Initially limited mostly to medical oncologists and radiotherapists, investigators now include urologists following the establishment of an agreement with the French Association of Urologists (AFU). The GETUG was able to complete the accrual of seven phase3 trials for PCa patients with localised disease, biochemical failure, and metastases over the past 20 yr. Five other phase 3 trials are currently accruing patients (including GETUG-AFU 21/PEACE 1 and GETUG-AFU 23/PEACE 2).

The NCRI Prostate Cancer Clinical Studies Group is an umbrella group run via the UK NCRI and developed from a previous long-standing organisation. Membership is multidisciplinary (oncology, surgery, radiology, pathology, patient groups, statistics), and leadership is on a rotational basis. The group provides a forum for discussion of planned and ongoing trials but has no funding to support trials, which must be sought elsewhere.

The SOGUG was created in 1998 from a national group of GU oncologists to coordinate and carry out cooperative studies in Spain, promote specific programs of study and research in GU cancers, and help standardise treatment nationwide. SOGUG members are currently involved in two phase 2 (one of them a randomised study) PCa studies and have contributed to international industry-sponsored studies of metastatic castration-resistant prostate cancer (CRPC). They are joining the two PEACE studies in hormone-naive metastatic and high-risk localised disease.

The SAKK-GU Group was formed within SAKK in the 1980s, and in 2007, it evolved into the SAKK Urogenital Tumors Project Group. Members include urologists, oncologists, radiation oncologists, pathologists, and basic researchers from public and private centres across all three language regions of Switzerland. As well as holding four meetings a year, mainly focussed on PCa, and fostering collaboration and communication between disciplines, the group has initiated and completed several clinical phase 2 clinical trials. Members also participate in international trials such as Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficiency (STAMPEDE).

The DUOS Group is a multidisciplinary study group in The Netherlands founded in 2010. Its key interest is initiating and collaborating in investigator- and industry-initiated and sponsored clinical trials in urologic cancers. These encompass the full range of metastatic and nonmetastatic phase 1–3 clinical trials, as well as postmarketing (phase 4 health-economic studies). DUOS collaborates with other national groups in Europe, such as the Scandic Group and the SOGUG, as well as Oncology Trials Insights in the United States.

The Irish Clinical Oncology Research Group has developed a genitourinary branch that plans to participate actively in large academic phase 3 trials sponsored in Europe and North America.

ARO was founded in 1980 as one of three task force groups of the German Cancer Society (DKG). A major goal of ARO is to conduct prospective randomised phase 3 clinical trials. ARO focusses on clinical research into lung, prostate, head-and-neck, breast, and rectal carcinoma. Nearly 20 studies are active. AUO was founded in 1991 as the Uro-oncology Task Force Group of the DKG.

3.2. Past and planned or ongoing phase 3 trials for prostate cancer patients in Europe

Table 1 and Table 2summarise past and planned or ongoing academic phase 3 trials conducted in Europe for patients with PCa, respectively.

3.3. Establishing a transcontinental network for prostate cancer research: introducing Prostate Cancer Consortium in Europe

PEACE was established in 2013 to facilitate large academic clinical trials in PCa, specifically phase 3 studies, in Europe. The initiative owes its origins to the realisation that two large phase 3 clinical trials were needed to answer questions related to the use of two new additions to therapy options for PCa: abiraterone and cabazitaxel. These studies, now called PEACE 1 and 2 ( Table 3 ), are the first large phase 3 trials to be carried out under the PEACE banner and were both launched in 2013.

Table 3 Summary of the ongoing Prostate Cancer Consortium in Europe phase 3 trials

Trial name PCa stage Planned no. of patients Question addressed by the trial Primary end point Status (planned or ongoing) Clinicaltrials.gov number
PEACE 1 Newly diagnosed metastatic 916 Addition of abiraterone, local RXT to ADT PFS and OS Ongoing NCT01957436
PEACE 2 High-risk localised (at least 2 high-risk criteria) 1050 Role of cabazitaxel,

pelvic RXT in patients treated with ADT and RXT
cPFS Ongoing EudraCT: 2012-000566-38

ADT = androgen-deprivation therapy; cPFS = clinical progression-free survival; OS = overall survival; PCa = prostate cancer; PEACE = Prostate Cancer Consortium in Europe; PFS = progression-free survival; RXT = radiation therapy.

PEACE 1 is a prospective randomised phase 3 factorial design study of ADT with or without local RXT, with or without abiraterone acetate and prednisone, in patients with metastatic hormone-naive PCa. It is planned to recruit 916 patients. A primary end point analysis (OS and PFS with events defined as the onset of CRPC or death) is expected 5.5 yr after inclusion of the first patient.

PEACE 2 is a randomised phase 3 factorial design study of cabazitaxel and RXT directed to pelvic lymph nodes in patients with localised PCa and at least two high-risk features of relapse. It is planned to recruit 1048 patients. Evaluation of clinical PFS will be carried out every year, except in the absence of biochemical failure (Phoenix criteria), and it will be repeated in case of PSA progression according to the Phoenix criteria and at each subsequent PSA progression. Duration of treatment will be 3 yr, and each patient will be followed up for 10 yr after completing treatment.

PEACE 1 and 2 include ancillary translational and radiographic studies. The PEACE 1 and 2 coordinating committees have two members from each of the international and national groups whose members are taking part (eg, GETUG, SOGUG). Members are chosen to represent the various specialties represented in the trials (medical oncologists, urologists, and radiotherapists). The two trials are sponsored by UNICANCER, the group that brings together 20 French cancer centres. Funding was obtained from both academic and industrial sources.

For future PEACE trials, it is planned that lead investigators (medical oncologists, radiation oncologists, and urologists) will develop protocols within national GU or other groups with an interest in PCa and acquire local or national academic sponsorship (eg, university, hospital, or organisation). They will then bring plans to PEACE that will provide access to its pan-European network of contributing GU and PCa groups and potential investigators. Funding will need to be secured by the sponsor and the trial chair and can be obtained from academic or industrial sources. To obtain a PEACE number, a study must (1) be a prospective trial on patients with PCa (any stage), (2) be conducted in Europe (although other countries can participate), (3) involve at least two European countries, and (4) have an academic sponsor. PEACE has no nationality of its own. Instead, it acts as a pan-European access portal for clinicians committed to and involved in PCa research.

An example of such a trial is the forthcoming PEACE 3 study, a randomised multicentre phase 3 trial comparing enzalutamide with a combination of radium-223 and enzalutamide alone in asymptomatic or mildly symptomatic CRPC patients with bone metastases. To fit the strategy of the GUCG group, it will include research on imaging of bone metastases and also study the value of post-progression response and second progression patterns as surrogate factors for drug combination registration.

3.4. Discussion

Major phase 3 trials leading to changes in practice have been successfully conducted in Europe in the last two decades[5], [6], [7], [8], [9], and [10]. Bringing together PCa specialists from across Europe into a single research organisation can help ensure that large phase 3 clinical trials are carried out in a timely, efficient, and cost-effective way. It can avoid duplication of effort and reduce the risk that important questions remain unanswered because of recruitment problems when studies have to rely on the enthusiasm and goodwill of a small number of hard-pressed local cancer centres and their patients.

The concept of establishing a transcontinental network of specialist cancer researchers is not unique. For example, in the United States, SWOG is one of the largest of the five clinical trial cooperative groups of the National Cancer Institute (NCI) and has >4000 affiliated physician researchers. Although it started in the southwestern United States, SWOG now extends to cancer centres in Canada, Sweden, and Saudi Arabia, and approximately 5000 patients are enrolled in its trials each year. Overall, >35 000 men were enrolled in SWOG's Selenium and Vitamin E Cancer Prevention Trial (SELECT) of PCa prevention [11] . The Canadian Cancer Society Research Institute (formerly the National Cancer Institute of Canada) Clinical Trials Group is a cooperative oncology group that comprises >80 member institutions that has conducted important practice-changing phase 3 trials[12], [13], and [14]. In Australia and New Zealand, the Trans-Tasman Radiation Oncology Group (TROG) has grown to >240 radiation oncologist members. More than 7000 patients have been recruited into TROG trials including TROG 96.01, Australia and New Zealand's largest cancer trial to date, with >800 men with inoperable PCa. In other cancers, the disease-specific Breast International Group (BIG) is a nonprofit organisation for academic breast cancer research groups worldwide that was founded in 1999. It now constitutes a network of 49 collaborative groups based in Europe, Canada, Latin America, Asia, and Australasia, with ties to several thousand specialised hospitals and research centres worldwide. About 30 clinical trials are run or are under development under the BIG umbrella, and BIG works closely with the US NCI and the North American Breast Cancer Group. The Australasian Lung Cancer Trials Group is a multidisciplinary organisation carrying out lung and thoracic cancer trials in Australia and New Zealand and currently has four phase 3 trials under way. The Australasian Gastrointestinal Trials Group is Australia's largest independent organisation carrying out clinical trials in gastrointestinal cancer with members also recruiting to four phase 3 trials.

It is of utmost importance that patients have access to clinical research and thus to innovative treatment modalities. Participation in clinical trials has been proven as the best available treatment and enhances quality of care even for patients treated outside of clinical studies. This is even true for countries with universal and rapid access to health care services [43] . From a public health point of view this can be facilitated by lowering the bureaucracy imposed on clinical research in recent years and/or by a supply of adequate resources. For example, the United Kingdom made the decision several years ago to centrally support approved academic trials with a consequent marked improvement in recruitment. The enlarged infrastructure also then benefits the commercial trials sector by instilling a culture of research as an intrinsic function of the health care system. If other EU countries took similar steps, international collaboration could be hugely facilitated.

The problem of excessive bureaucracy in setup still remains, with the need for multiple permissions to open trials in different countries. A pan-European system of approvals is urgently needed to facilitate international trials, coupled with regulatory changes to allow cross-recognition of clinical trials authorisations for investigational medical products. The only aspect of a trial that is nation specific is the patient information sheet, which clearly needs to be in the local language. Data protection regulations also need to be modified to allow easy and rapid sharing of data between health care and academic settings subject to appropriate ethical oversight. Such transfers could speed trial data collection and reduce costs but are currently impeded by large bureaucratic barriers.

4. Conclusions

The EU [44] and other countries [45] have undertaken some steps to foster international collaboration of clinical cancer research to allow both patient access to new treatment options and faster generation of data. The PEACE consortium is now joining the efforts to achieve these goals in the European fight against PCa, but much still needs to be done both at the national government level and within the EU administration to facilitate a more research-friendly environment.

The prospect of setting up a comparable clinical trials group in PCa for Europe is not without its challenges. But recent decades have seen a significant expansion in communication between the different specialties involved in the care of people with PCa and between specialists in different parts of Europe. As PEACE 1 and 2 are under way, we hope that interest in these and further studies will rapidly increase and the current network of PEACE investigators will extend across Europe.


Author contributions:Karim Fizazi had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design:Fizazi.

Acquisition of data:Fizazi, Abrahamsson, Ahlgren, Bellmunt, Castellano, Culine, de Wit, Gillessen, Gschwend, Hamdy, James, McDermott, Miller, Wiegel, Wirth, Tombal.

Analysis and interpretation of data:Fizazi.

Drafting of the manuscript:Fizazi.

Critical revision of the manuscript for important intellectual content:Fizazi, Abrahamsson, Ahlgren, Bellmunt, Castellano, Culine, de Wit, Gillessen, Gschwend, Hamdy, James, McDermott, Miller, Wiegel, Wirth, Tombal.

Statistical analysis:None.

Obtaining funding:None.

Administrative, technical, or material support:None.

Supervision:None.

Other(specify): None.

Financial disclosures:Karim Fizazi certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Karim Fizazi participates on advisory boards or is a speaker for Amgen, Astellas, Bayer, Ipsen, Janssen, Sanofi, and Takeda.

Funding/Support and role of the sponsor:None.

Acknowledgement statement:We thank Jenny Bryan for editing the manuscript.

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Footnotes

a Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France

b Department of Urology, Lund University, Lund, Sweden, and Malmö University, Malmö, Sweden

c Department of Medical Oncology, University Hospital del Mar, UPF University, Barcelona, Spain

d Department of Medical Oncology, University Hospital 12 de Octubre, Madrid, Spain

e Department of Medical Oncology, Hôpital Saint Louis, Paris, France

f Department of Medical Oncology, Erasmus Medical Centre Cancer Institute, Rotterdam, The Netherlands

g Department of Medical Oncology, Kantonsspital, St. Gallen, Switzerland

h Urologische Klinik und Poliklinik der Technischen Universität, München, Germany

i Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK

j Cancer Research Unit, University of Warwick, Coventry, UK

k Department of Medical Oncology, The Adelaide and Meath Hospital, Dublin, Ireland

l Klinik für Urologie, Charité-Universitätsmedizin Berlin, Berlin, Germany

m Department of Radiation Oncology, University Hospital Ulm, Ulm, Germany

n Department of Urology, University Clinic Carl Gustav Carus, Dresden, Germany

o Service d’Urologie, Institut de Recherche Clinique, Université Catholique de Louvain, Louvain-la-Neuve, Belgium

lowast Corresponding author. Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, 114 rue Edouard Vaillant, 94800 Villejuif, France. Tel. +33 1 42 11 43 17; Fax: +33 1 42 11 52 17.

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