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Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database
EUF-34; No. of Pages 12 EUROPEAN UROLOGY FOCUS XXX (2015) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Prostate Cancer
Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database Alexandros Tsikkinis a, Nikola Cihoric a, Gianluca Giannarini b, Stefan Hinz c, Alberto Briganti d, Peter Wust e, Piet Ost f, Guillaume Ploussard g, Christophe Massard h, Cristian I. Surcel i, Prasanna Sooriakumaran j, Hendrik Isbarn k, Peter J.L. De Visschere l, Jurgen J. Futterer m, Roderick C.N. van der Bergh n, Alan Dal Pra a, Daniel M. Aebersold a, Volker Budach e, Pirus Ghadjar e,* a
Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland; b Department of Urology, University of
Udine, Udine, Italy;
c
Department of Urology, Charite´ Universita¨tsmedizin Berlin, Berlin, Germany;
d
Unit of Urology/Division of Oncology, Ospedale
San Raffaele, Milan, Italy; e Department of Radiation Oncology, Charite´ Universita¨tsmedizin Berlin, Berlin, Germany; f Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, Ghent, Belgium; g Department of Urology, Saint-Louis Hospital, Paris, France;
h
Institut Gustave
Roussy, University of Paris Sud, Villejuif, France; i Centre of Urological Surgery, Dialysis and Renal Transplantation, Fundeni Clinical Institute, Bucharest, Romania; j Surgical Intervention Trials Unit, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; k Regio Clinicum Wedel, Department of Urology and Martini-Clinic, Prostate Cancer Center, Hamburg-Eppendorf, Germany; l Department of Radiology, Division of Genitourinary Radiology, Ghent University Hospital, Ghent, Belgium; m Department of Radiology, Radboud University, Nijmegen Medical Centre, Nijmegen, The Netherlands; n Department of Urology, University Medical Centre Utrecht, Utrecht, The Netherlands
Article info
Abstract
Article history: Accepted May 5, 2015
Background: It is not easy to overview pending phase 3 trials on prostate cancer (PCa), and awareness of these trials would benefit clinicians. Objective: To identify all phase 3 trials on PCa registered in the ClinicalTrials.gov database with pending results. Design and setting: On September 29, 2014, a database was established from the records for 175 538 clinical trials registered on ClinicalTrials.gov. A search of this database for the substring ‘‘prostat’’ identified 2951 prostate trials. Phase 3 trials accounted for 441 studies, of which 333 concerned only PCa. We selected only ongoing or completed trials with pending results, that is, for which the primary endpoint had not been published in a peer-reviewed medical journal. Results and limitations: We identified 123 phase 3 trials with pending results. Trials were conducted predominantly in North America (n = 63; 51%) and Europe (n = 47; 38%). The majority were on nonmetastatic disease (n = 82; 67%), with 37 (30%) on metastatic disease and four trials (3%) including both. In terms of intervention, systemic treatment was most commonly tested (n = 71; 58%), followed by local treatment 34 (28%), and both systemic and local treatment (n = 11; 9%), with seven (6%) trials not classifiable. The 71 trials on systemic treatment included androgen deprivation therapy (n = 34; 48%), chemotherapy (n = 15; 21%), immunotherapy (n = 9; 13%), other systemic drugs (n = 9; 13%), radiopharmaceuticals (n = 2; 3%), and combinations (n = 2; 3%). Local treatments tested included radiation therapy (n = 27; 79%), surgery (n = 5; 15%), and both (n = 2; 2%). A limitation is that not every clinical trial is registered on ClinicalTrials.gov. Conclusion: There are many PCa phase 3 trials with pending results, most of which address questions regarding systemic treatments for both nonmetastatic and metastatic
Associate Editor: James Catto Keywords: Prostate cancer Trials ClinicalTrials.gov Prospective
* Corresponding author. Department of Radiation Oncology, Charite´ Universita¨tsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. Tel. +49 30 450 657055; Fax: +49 30 450 7527152. E-mail address: [email protected] (P. Ghadjar). http://dx.doi.org/10.1016/j.euf.2015.05.003 2405-4569/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
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EUROPEAN UROLOGY FOCUS XXX (2015) XXX–XXX
disease. Radiation therapy and androgen deprivation therapy are the interventions most commonly tested for local and systemic treatment, respectively. Patient summary: This report describes all phase 3 trials on prostate cancer registered in the ClinicalTrials.gov database with pending results. Most of these trials address questions regarding systemic treatments for both nonmetastatic and metastatic disease. Radiation therapy and androgen deprivation therapy are the interventions most commonly tested for local and systemic treatment, respectively. # 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
1.
Introduction
trials were still considered as having pending results and included in the analysis.
Changes in clinical practice are commonly driven by results from randomized phase 3 trials. While published trial results are summarized by guideline recommendations and textbooks with a certain time delay, it is less easy to overview phase 3 trials that have not yet reported their primary endpoint(s), that is, ongoing trials or trials that have completed accrual but need additional follow-up time for data maturity and manuscript development and publication. Awareness of these pending trials could help avoid duplication of trials and a waste of scarce resources. It might also provide clinicians with an idea of important questions to be answered in the near future and questions that have not yet been asked, and at the same time acknowledge which phase 3 trials have failed and the reasons that led to such failure. To the best of our knowledge, this is the most comprehensive assessment of ongoing phase 3 research in prostate cancer. ClinicalTrials.gov is the most robust of the international public clinical trial registries and has already proven useful for systematic analyses [1]. Completed and ongoing European phase 3 trials on prostate cancer have recently been reviewed according to expert opinion [2]. In the present study we attempt to build on these results using a worldwide approach that involves a systematic analysis of the ClinicalTrials.gov database. 2.
Materials and methods
The records for 175 538 clinical trials registered on ClinicalTrials.gov were downloaded on September 29, 2014 and a database was established. We searched this database for the substring ‘‘prostat’’. In total, 2951 prostate trials were identified. Phase 3 trials accounted for 441 studies, of which 333 concerned only prostate cancer. Trials covering multiple tumor entities, as well as prostate cancer prevention trials, were excluded. We then identified (1) trials that were active but not yet recruiting; (2) trials that were active and recruiting; and (3) trials that had been completed for which the primary endpoint had not been objectively published in a peer-reviewed medical journal (Fig. 1). This process was achieved via manual crosschecking on with www.pubmed.org by searching for English peer-reviewed original publications describing results for the primary trial endpoint using appropriate follow-up duration and sample size. Completed trials for which accrual had finished >10 yr previously were excluded, as it was assumed that results for these trials will never be published. In addition, the Internet was browsed for conference abstracts and the ClinicalTrials.gov registry was searched for uploaded references or trial results for the primary trial endpoint. If a conference abstract was found or trial results were available within the registry, but no peerreviewed original publication was identified, this was noted and such
The location in which each trial was conducted was noted from the ClinicalTrials.gov database according to the location of the principal investigator or the corporate headquarters of the leading sponsor agency. Trials were also grouped according to the primary intervention (systemic vs local vs both systemic and local treatments) and disease stage (metastatic vs nonmetastatic disease). Trials testing local treatments (radiation therapy, surgery, or a combination of the two) were subclassified according to patient risk profile (low-risk vs intermediaterisk vs high-risk). All trials were then further subclassified according to clinical states model recommended by the Prostate Cancer Clinical Trials Working Group (PCWG2). The clinical states model categorizes the disease continuum and allows more detailed characterization of prostate cancer patients according to five different groups. This was done to provide readers with an overview of the different disease states investigated in the trials (Supplementary Table 1) [3].
3.
Results
We identified 123 phase 3 trials with pending results. The trial characteristics are summarized in Table 1. Results concerning the primary trial endpoint have been presented in abstract form for seven of these trials. The trials were predominantly performed in North America (n = 63; 51%). More than one third of trials were carried out in each of the USA (n = 50; 41%) and Europe (n = 47; 38%). France (n = 14; 11%) and Switzerland (n = 6; 5%) together accounted for almost half of all European trials. Only nine trials were conducted in Asia (7%) and four in Australia (3%) (Fig. 2). Industry funding was almost exclusively for systemic treatments (31 trials). By contrast, industry funding was provided for just one trial investigating radiation therapy and no surgery trials. There was a more even distribution of funding by universities, hospitals, and research groups and agencies (79 trials), with funding for 44 trials investigating systemic therapies and 38 trials assessing local therapies. The 123 trials were supported by 82 individual sponsors. The Radiation Therapy Oncology Group (RTOG) sponsored the greatest number of trials (n = 10; 8%), followed by the privately funded French Unicancer Group (n = 7; 6%). The majority of trials were conducted for patients with nonmetastatic disease (n = 82, 67%), followed by patients with metastatic disease (n = 37, 30%). The remaining four trials (3%) tested both metastatic and nonmetastatic disease. Among the 123 trials, 71 (58%) tested some form of systemic treatment (Table 2), 34 (28%) tested local
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
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EUROPEAN UROLOGY FOCUS XXX (2015) XXX–XXX
Complete ClinicalTrials.gov database n = 175 538
29.09.14
Trial identification using the substring "prostat" within the subset "Conditions"
All prostate-related trials n = 2 951
Prostate "phase 3" trial identification
All phase 3 prostate trials n = 441
Prostate "cancer" trial identification
Excluded
Other non–cancer-related prostate trials or multiple tumor entities
n = 108
All phase 3 Prostate cancer trials n = 333
02.11.14
Manual categorization
Excluded
Excluded
Terminated/suspended/nonrandomized trials with primary endpoint/s not published
Completed trials with published primary endpoint/s n = 141
Randomized phase 3 trials with primary endpoint/s not published
n = 69
n = 123
Fig. 1 – Flow diagram of the database search.
treatment (Table 3), and 11 (9%) tested both systemic and local treatments (Table 4). The disease state according to PCWG2 recommendations is listed for treatment interventions in Supplementary Table 1. In total, 101 882 patients
were expected to be randomized, with more than half of these randomized in trials testing systemic therapies (n = 54 754; 54%). Trials testing local treatments accounted for 27% of all patients (n = 27 306) and the remaining
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
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EUROPEAN UROLOGY FOCUS XXX (2015) XXX–XXX
Table 1 – Trial characteristics
a
Trial attribute
Trials, n (%) All (n = 123)
Lead sponsor Industry University Hospital or center Group or agency Other Masking Open Single blind Double blind NA Number of arms 1 2 3 4 NA Enrollment 0–100 101–500 501–1000 >1000 Location North America Europe Asia Oceania a
Systemic therapy (n = 82)
Radiation therapy (n = 39)
Surgery (n = 9)
Others (n = 7)
32 20 25 34 12
(26) (16) (20) (28) (10)
31 11 11 22 7
1 5 11 15 7
0 3 1 4 1
0 3 0 3 1
83 6 26 8
(67) (5) (21) (7)
50 1 24 7
35 3 0 1
7 2 0 0
5 0 2 0
2 94 7 7 13
(2) (76) (6) (6) (10)
2 59 7 5 9
0 28 3 4 4
0 7 1 1 0
0 4 0 1 2
9 54 30 31
(7) (44) (24) (25)
5 32 22 23
3 16 8 12
1 3 1 4
0 5 2 0
63 47 9 4
(51) (28) (7) (3)
39 33 8 2
22 15 1 1
4 5 0 0
3 3 0 1
Some trials included more than one intervention, so the number of trials summed for interventions may be greater than the total number of trials.
19% were randomized in trials testing both systemic and local treatments (n = 19,822). Radiation therapy was tested alone or as a component in 39 (32%) trials. The majority of these 39 trials used intensity-modulated radiation therapy (n = 27; 69%); seven
(18%) trials investigated hypofractionated treatment schedules (data not shown). Surgery was a component in nine (7%) trials. Seven trials (n = 7; 6%) tested miscellaneous activities that could not be assigned to any specific category (Table 1, Fig. 3).
Fig. 2 – Heat map describing the locations where trials were conducted. An interactive version of the map can be accessed at http://jsfiddle.net/ pvpnz41o/6/embedded/result/.
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
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EUROPEAN UROLOGY FOCUS XXX (2015) XXX–XXX
Table 2 – Trials investigating systemic treatments (n = 71; total accrual expected 54 754) ClinicalTrials.gov
Short name
Chemotherapy (n = 15; 7316 patients) Patient preference between NCT02044354 cabazitaxel and docetaxel in MCRPC NCT00796458 NCT00436839 NCT01522443
NCT00764166
ADT with or without docetaxel for advanced PCa Taxotere PCa new indication registration trial in China Cabozantinib (XL184) vs mitoxantrone + prednisone in men with previously treated symptomatic CRPC Prospective randomized phase 3 study comparing ADT docetaxel
Start date (D/M/Y)
Planned accrual
1/1/2014
174
4/5/2014
200
1/1/2007
228
3/1/2012
246
6/1/2003
254
NCT00132301
Chemotherapy after prostatectomy (CAP) for high-risk PCa
6/1/2006
298
NCT00116142
ADT and RT for 6 mo docetaxel for high-risk PCa
6/1/2005
350
NCT00653848
Treatment of PCa with docetaxel + ADT vs ADT alone in patients treated with RP Docetaxel compared with observation in treating patients who have undergone RP for PCa Efficacy study evaluating chemotherapy In PCa
5/1/2007
378
10/1/2005
396
11/12/2014
400
ADT + RT or ADT + RT followed by docetaxel and prednisone in treating patients with localized PCa Comparison of cabazitaxel/ prednisone alone or with custirsen for second-line chemotherapy in PCa CHAARTED: chemohormonal therapy vs ADT randomized trial for extensive disease in PCa Cabazitaxel vs docetaxel both with prednisone in patients with MCRPC
12/1/2005
612
8/12/2014
630
7/1/2006
780
5/1/2011
1170
Cabazitaxel 20 mg/m2 compared to 25 mg/m2 with prednisone for the treatment of MCRPC ADT (n = 34; 35 604 patients) NCT00553878 Comparing 0.5 mg dutasteride vs placebo daily in men receiving ADT for PCa
4/11/2014
1200
NCT00376792
NCT01978873
NCT00288080
NCT01578655
NCT00309985
NCT01308567
NCT01308580
3/1/2007
100
NCT01398657
Cryotherapy with or without shortterm adjuvant ADT in PCa
7/1/2011
182
NCT01492972
Hypofractionated proton RT with or without ADT for intermediate-risk PCa Study of abiraterone acetate plus prednisone in MCRPC patients after failed docetaxel chemotherapy
1/1/2012
192
8/12/2014
214
Study to compare the effect of ASP3550 with goserelin in patients with PCa Effect of Enantone LP 11.25 mg (leuprorelin) on histologic progression of indolent PCa
8/13/2014
230
3/1/2013
240
NCT01695135
NCT01964170
NCT02085252
Question addressed
Evaluate patient preference between cabazitaxel and docetaxel in first-line chemotherapy for MCRPC Evaluate BPFS for ADT + docetaxel vs ADT alone in advanced PCa Compare docetaxel + prednisone vs mitoxantrone + prednisone in MCRPC Compare pain and bone scan responses for cabozantinib vs mitoxantrone + prednisone in CRPC Evaluate PFS of high-risk metastasisfree PCa in patients treated with ADT for 1 yr docetaxel after prior RP or RT Evaluate efficacy of early adjuvant chemotherapy for PCa potentially cured by RP but at high risk of relapse Determine if there is an OS benefit when adding docetaxel to ADT and RT for high-risk PCa Effectiveness of adjuvant docetaxel after RT to prevent early relapse in intermediate- and high-risk PCa Compare BPFS for docetaxel vs surveillance after RP with positive margins Is there a benefit of adding cabazitaxel before ADT vs ADT alone in metastatic or high-risk PCa Compare OS for ADT and RT followed by docetaxel and prednisone vs ADT and RT alone for localized PCa Addition of custirsen to cabazitaxel/ prednisone slows tumor progression and enhances OS vs cabazitaxel/ prednisone alone in MCRPC ADT with or without chemotherapy in treating patients with metastatic PCa Improved OS with cabazitaxel + prednisone vs docetaxel + prednisone in chemo-naive MCRPC OS noninferiority of cabazitaxel 20 mg/m2 vs 25 mg/m2 in docetaxeltreated MCRPC Daily dutasteride 0.5 mg could increase the off-treatment interval in men under intermittent ADT for localized PCa Compare PFS for cryoablation alone vs cryoablation plus ADT in high-risk localized PCa Examine the benefit of adding ADT To hypofractionated proton RT vs proton RT alone with regard to failure Evaluate safety and BPFS efficacy of abiraterone acetate plus prednisone in Asian MCRPC patients after failed docetaxel-based chemotherapy Compare the safety and efficacy of degarelix vs goserelin in patients with PCa Assess leuprorelin vs active surveillance without ADT for indolent PCa and compare their therapeutic benefit for low-risk localized PCa
Status
Recruiting
Recruiting Completed Active, not recruiting
Active, not recruiting
Active, not recruiting
Recruiting
Recruiting
Recruiting
Recruiting
Active, not recruiting
Recruiting
Recruiting
Active, not recruiting
Active, not recruiting
Active, not recruiting
Recruiting
Recruiting
Active, not recruiting
Active, not recruiting
Recruiting
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
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Table 2 (Continued ) ClinicalTrials.gov
Short name
Start date (D/M/Y)
Planned accrual
Question addressed
Status
Compare the efficacy and safety of degarelix for 1 mo vs goserelin in Chinese patients with PCa requiring ADT Compare BPFS for abiraterone acetate plus prednisone vs placebo in MCRPC
Active, not recruiting
Evaluate the potential additional impact on BPFS of 2 yr of ADT with goserelin vs goserelin for 4 mo plus daily bicalutamide for 2 mo for highrisk PCa Investigate the safety and BPFS efficacy of intermittent vs continuous degarelix for PCa with prior treatment failure after localized treatment Study whether additional adjuvant GnRH agonist therapy improves BPFS
Active, not recruiting
NCT01744366
1-mo degarelix/comparator treatment for PCa in a Chinese population
1/1/2013
280
NCT01591122
Study of abiraterone acetate plus prednisone in patients with chemonaive MCRPC Trial of adjuvant ADT in combination with 3D-conformal RT doses in high- and intermediaterisk localized PCa.
3/1/2012
313
11/5/2014
358
NCT00928434
Study of degarelix in patients with PCa
5/1/2009
405
NCT00664456
Neoadjuvant GnRH agonist therapy and permanent 125I implants adjuvant GnRH agonist therapy in previously untreated intermediaterisk PCa Triptorelin, flutamide, and EBRT or EBRT alone in treating stage II or III PCa RT with or without goserelin for patients who have undergone surgery for recurrent or refractory PCa ADT in treating patients with stage I or II PCa
4/8/2014
420
7/1/2004
450
Studying the efficacy of NA ADT with EBRT vs EBRT alone
Recruiting
10/1/2006
466
Compare OS for adjuvant RT with ADT vs without ADT in recurrent or refractory PCa
Recruiting
6/1/1999
496
Determine the effectiveness of ADT for 1 yr vs no ADT for PCa at high risk of recurrence after RP OS comparison of ADT withdrawal vs maintenance and intermittent vs continuous chemotherapy in CRPC Compare survival for 18 mo vs 36 mo of ADT combined with pelvic RT in high-risk PCa Compare BPFS for intermittent vs continuous ADT in relapsing and locally advanced PCa Compare the BPFS effectiveness of RT with ADT vs without ADT in localized PCa Compare OS for RT with ADT vs without in stage II,III, or biochemically recurrent PCa after RP Compare the efficacy and safety of 3mo degarelix dosing regimen vs goserelin acetate Compare OS for dose-escalated RT and standard ADT (GnRH agonist) vs enhanced ADT (GnRH agonist+TAK700) Compare OS for orteronel + prednisone vs placebo + prednisone in MCRPC Comparing Time To Androgen Independent Disease Of Immediate Vs Deferred ADT For Recurrent PCa After RP Compare OS for Abiraterone acetate plus low-dose prednisone plus ADT vs ADT alone in MCRPC Evaluate the efficacy and safety of ARN-509 vs placebo in high-risk nonMCRPC Compare OS for enzalutamide alone vs enzalutamide, abiraterone acetate and prednisone in MCRPC
Active, not recruiting
NCT02175212
NCT00104741
NCT00423475
NCT00003645
NCT01224405
PCa ADT withdrawal and intermittent chemotherapy
4/10/2014
600
NCT00223171
Duration of ADT combined with pelvic RT in PCa
10/1/2000
650
NCT00378690
Phase 3b study of intermittent vs continuous ADT with ELIGARD
3/1/2006
706
NCT00021450
RT with or without bicalutamide and goserelin in treating patients with PCa RT with or without bicalutamide in treating patients with stage II, III, or recurrent PCa A trial of degarelix in patients with PCa
4/1/2014
800
2/1/1998
840
6/1/2009
859
900
NCT00002874
NCT00946920
NCT01546987
ADT, RT, and steroid 17-amonooxygenase TAK-700 in treating high-risk PCa
5/1/2012
NCT01193257
Study comparing orteronel plus prednisone in patients with MCRPC
11/10/2014
1099
NCT00439751
Immediate vs deferred ADT for recurrent PCa after radical RT
4/7/2014
1100
NCT01715285
Study of abiraterone acetate plus low-dose prednisone plus ADT vs ADT alone for MCRPC Study of ARN-509 in men with nonMCRPC
2/1/2013
1200
9/13/2014
1200
1/1/2014
1224
NCT01946204
NCT01949337
Enzalutamide with or without abiraterone acetate and prednisone in treating patients with MCRPC
Active, not recruiting
Completed
Active, not recruiting
Active, not recruiting
Active, not recruiting
Completed
Active, not recruiting
Active, not recruiting
Completed
Recruiting
Completed
Active, not recruiting
Recruiting
Recruiting
Recruiting
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
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Table 2 (Continued ) ClinicalTrials.gov NCT01193244
NCT01809691
NCT02200614
NCT00936390 NCT02003924
NCT00005044
NCT00110162
Short name
NCT02111577
Question addressed
Status
Evaluate PFS and OS for orteronel + prednisone vs placebo + prednisone in MCRPC Compare OS in metastatic PCa randomly assigned to ADT plus orteronel vs ADT plus bicalutamide Comparing metastasis-free survival for OMD-201 vs placebo in high-risk non-MCRPC Compare OS for RT with ADT for 6 mo vs without ADT Compare metastasis-free survival for enzalutamide vs placebo in nonMCRPC Disease-specific survival for ADT for 8 wk vs 28 wk followed by RT with concurrent ADT in intermediate-risk PCa Compare the timing of intervention with ADT in PCa with rising Evaluating metastasis-free survival for 24-mo adjuvant ADT vs surveillance after RP
Active, not recruiting
10/1/2010
1454
3/1/2013
1486
Efficacy and safety study of ODM201 in men with high-risk nonMCRPC RT with or without ADT in treating patients with PCa Safety and efficacy study of enzalutamide in patients with nonMCRPC ADT And RT in treating patients with PCa
9/14/2014
1500
9/9/2014
1520
12/1/2013
1560
2/1/2000
1579
10/1/2004
2000
1/6/2011
700
5/1/2010
600
9/11/2014
711
11/9/2014
760
6/1/2012
960
ADT in treating patients with PCa
Benefit evaluation of adjuvant ADT for 24 mo after RP in patients with high risk of recurrence Immunotherapy (n = 9; 8281 patients) Phase 3 study of immunotherapy to NCT01057810 treat advanced PCa Study of ProstAtak immunotherapy NCT01436968 with standard RT for localized PCa
NCT01605227
Planned accrual
Study comparing orteronel plus prednisone in patients with chemotherapy-naive MCRPC S1216, ADT + orteronel vs ADT + bicalutamide for metastatic PCa
NCT01442246
NCT00925600
Start date (D/M/Y)
Compare lens opacification in nonmetastatic PCa receiving denosumab for bone loss due to ADT Study of cabozantinib (XL184) vs prednisone in men with MCRPC previously treated with docetaxel and abiraterone or MDV3100 Study of DCVAC added to standard chemotherapy for men with MCRPC
4/14/2014
1170
NCT01234311
A study of tasquinimod in men with MCRPC
3/1/2011
1200
NCT02057666
Study of tasquinimod in Asian chemo-naive patients with MCRPC
1/1/2014
300
Efficacy trial of PROSTVAC-V/F GM-CSF in men with asymptomatic or minimally symptomatic MCRPC Prevention of symptomatic skeletal NCT02051218 events with denosumab administered every 4 wk vs 12 wk Radiopharmaceuticals (n = 2; 825 patients) NCT00024167 Chemotherapy with or without strontium-89 in treating patients with PCa Phase 3 radium-223 MCRPC-PEACE NCT02194842 3 Trial NCT01322490
Other systemic drugs (n = 9; 1808 patients) GTN therapy on biomarkers of NCT01704274 immune escape in men with biochemical recurrence of PCa Zoledronic acid for the prevention NCT00058188 of bone loss in men with PCa on long-term ADT NCT01006395
Prevention of microarchitectural bone decay in males with nonmetastatic PCa receiving ADT
11/11/2014
1200
7/1/2014
1380
4/2/2014
265
12/1/2014
560
4/12/2014
60
3/1/2003
70
1/1/2011
100
Compare OS for ipilimumab vs placebo in MCRPC Evaluate the effectiveness of ProstAtak immunotherapy + RT vs placebo + RT for localized PCa Compare lens opacification in nonmetastatic PCa receiving denosumab for bone loss due to ADT vs placebo Evaluate the effect of cabozantinib vs prednisone on OS in men with previously treated MCRPC Evaluate the OS efficacy and safety of DCVAC with standard chemotherapy vs placebo in MCRPC Confirm the effect of tasquinimod on delaying disease progression compared with placebo in MCRPC Confirm the effect of tasquinimod in delaying disease progression or death vs placebo in chemo-naive MCRPC Determine whether PROSTVAC alone or combined with GM-CSF can prolong OS in MCRPC Test if the benefit of denosumab is maintained if administered every 12 wk vs every 4 wk
Recruiting
Recruiting
Recruiting Recruiting
Active, not recruiting
Recruiting Active, not recruiting
Active, not recruiting Recruiting
Recruiting
Active, not recruiting
Recruiting
Active, not recruiting
Recruiting
Recruiting
Recruiting
Compare OS for chemotherapy with strontium-89 vs chemotherapy alone for bone-metastasized PCa Compare PFS for enzalutamide vs a combination of radium 223 and enzalutamide in MCRPC
Completed
Effect of transdermal GTN on biomarkers of immune escape in biochemically recurrent PCa Comparing the effectiveness of zoledronic acid combined with calcium vs calcium alone in preventing bone loss Compare bone microarchitectural changes when administering zoledronic acid vs placebo
Recruiting
Not yet recruiting
Active, not recruiting
Recruiting
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
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Table 2 (Continued ) ClinicalTrials.gov NCT00887432
NCT00426777
NCT00685646
NCT01864096
Short name Cholecalciferol supplement in treating patients with localized PCa undergoing observation Efficacy study of risedronate to prevent cancer treatment–induced bone loss in PCa ADT with or without zoledronic acid in treating patients with PCa and bone metastases Metformin Active Surveillance Trial (MAST) Study
NCT02220829
Comparative study of use of alphablockers to treat symptoms in PCa patients undergoing RT Study of zoledronic acid for patients NCT00242567 with hormone-sensitive bone metastases from PCa Combinations (n = 2; 920 patients) EBRT concurrent with docetaxel NCT01811810 and adjuvant short-course ADT NCT02043678
Radium-223 dichloride and abiraterone acetate compared to placebo and abiraterone acetate for PCa
Start date (D/M/Y)
Planned accrual
12/1/2009
100
1/1/2007
160
5/1/2008
200
10/1/2013
408
10/1/2014
188
12/1/2005
522
3/1/2013
120
3/1/2014
800
Question addressed
Status
Evaluate how well cholecalciferol supplementation works in regard to PSA response in localized PCa Evaluate the effect of risedronate vs placebo on bone mineral density in men undergoing ADT Study the time to treatment failure for ADT + zoledronic acid vs ADT alone in bone-metastasized PCa Can metformin can delay the time to progression in men with low-risk PCa vs placebo Compare standard of care in treating patients undergoing RT vs preventive treatment with Rapaflo Determine if early treatment with zoledronic acid is more efficacious than delayed treatment
Recruiting
Compare adverse effects of RT with docetaxel and short-course ADT vs RT with long-course ADT Determine if addition of radium-223 dichloride to standard treatment can prolong life and delay events specific for bone-metastasized PCa
Recruiting
Completed
Active, not recruiting
Recruiting
Not yet recruiting
Completed
Recruiting
PCa = prostate cancer; RT = radiotherapy; OS = overall survival; EBRT = external beam RT; LDR = low dose rate; RP = radical prostatectomy; ADT = androgen deprivation therapy; PSA = prostate-specific antigen; GnRH = gonadotropin-releasing hormone; BPFS = biochemical progression-free survival; NA = neoadjuvant; CRPC = castration-resistant prostate cancer; MCRPC = metastatic CRPC; DCVAC = dendritic cell vaccination; GTN = glyceryl trinitrate; GM-CSF = granulocyte-macrophage colony-stimulating factor.
Of the 71 trials testing systemic treatments alone, 34 (48%) tested androgen deprivation therapy (ADT). ADT duration was the question most commonly addressed, followed closely by optimal timing of ADT administration. This was followed by trials testing different types of chemotherapy (n = 15; 21%), immunotherapy (n = 9; 13%), and radiopharmaceutical (n = 2, 3%). Nine trials (13%) tested other systemic drugs and two (3%) tested a combination of systemic treatments (Table 2). In total, 23 trials were conducted on castration-resistant prostate cancer. Among the 34 trials investigating local treatments, radiation therapy was tested in 27 (79%), surgery alone in five (15%), and both radiation therapy and surgery in two (6%) trials (Table 3). The majority of trials on local treatments were conducted in intermediate-risk disease (n = 20; 59%), followed by low-risk (n = 15; 44%) and highrisk (n = 15; 44%) disease (data not shown). 4.
Discussion
Our results confirm that there is intense clinical trial activity on prostate cancer, with 123 phase 3 trials with pending results registered in the ClinicalTrials.gov database. Most trials identified were performed in North America or Europe and were designed to improve treatments for nonmetastatic prostate cancer (67%). More than half of all trials identified tested the effects of systemic treatment, some in patients with nonmetastatic disease. Given the awareness of the potential risks of overtreatment for
indolent prostate cancers [4,5], cure is not always achieved in patients with either aggressive localized, locally advanced, or locally recurrent disease [6]. This might be because at least some patients with nonmetastatic disease harbor micrometastatic disease. By contrast, patients with metastatic castration-resistant disease require more aggressive systemic therapy. Thus, improvements in systemic treatments even in the nonmetastatic setting are very important and might positively impact cancer control rates. Beside this clinical rationale, our finding that trials testing systemic treatments tended to be supported by industry may be another reason for the high rate of trials focusing on systemic treatments (even in nonmetastatic patients), reflecting certain company interests. Given the heterogeneity of patients with nonmetastatic prostate cancer, there is a need for improved patient stratification using novel biomarkers for prognostic and predictive guidance in deciding which patients would benefit most from which treatment approach, similar to the situation for breast and lung cancer. Unfortunately, it seems that phase 3 trials currently registered in the ClinicalTrials.gov database are not designed to improve this problem in the future, and are still only based on the TNM classification and Gleason grading systems. Trials focusing on local treatment methods much more commonly involved radiation therapy than surgery. This can be explained in part by technological innovations during the last two decades and the desire to validate
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
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Table 3 – Trials investigating local treatments (n = 34; total accrual expected 27 306) ClinicalTrials.gov
Short name
Surgery (n = 5; 2392 patients) Obese patient during RARP: NCT01868347 preemptive ventilator strategy NCT01825642 NCT01613651 NCT01555086 NCT01407263
Seminal vesicle–sparing and nervesparing RP RALP with or without pelvic drain placement Extended vs limited pelvic lymphadenectomy during RP Trial of modifications to RP
Multiple interventions (n = 2; 8800 patients) PREFERE trial NCT01717677 Surgery vs RT for locally advanced PCa Radiation therapy (n = 27; 16 114 patients) 3D-conformal RT vs tomotherapy NCT00326638 NCT02102477
Start date (D/M/Y)
Planned accrual
2/1/2013
40
9/6/2014
140
8/12/2014
312
1/8/2011
500
7/1/2011
1400
1/10/2012
7600
1/10/2014
1200
11/5/2014
72
Question addressed
Preemptive PEEP vs PEEP after pneumoperitoneum and Trendelenburg Seminal vesicle–sparing vs nervesparing RP RALP with pelvic drain vs without Extended vs limited pelvic lymphadenectomy Fascial suturing RP vs lymph node template RP
3/1/2013
75
NCT01411345
MRI-mapped dose-escalated salvage RT
6/1/2011
80
NCT01230866
Hypofractionated proton RT For low-risk PCa HDR vs LDR brachytherapy
11/10/2014
192
10/1/2013
200
NCT00084552
IMRT with decreased radiation dose to erectile tissue vs without
12/1/2003
200
NCT01538628
SpaceOAR system pivotal study
1/1/2012
222
NCT00667888
IMRT dose escalation using hypofractionation Hypofractionated, dose escalation RT ADT with elective nodal and doseescalated RT Proton therapy vs IMRT
1/1/2001
225
1/1/2012
250
5/1/2004
400
7/1/2012
400
6/1/2003
588
10/1/2005
600
1/1/1998
602
4/6/2014
1115
5/1/2006
1204
3/1/2002
1532
7/1/2011
2580
1/1/2011
350
6/1/2013
350
10/1/2008
500
Finding the optimal dose
NCT01617161
NCT00063882 NCT00247312
Brachytherapy with or without EBRT 103 Pd dose de-Escalation brachytherapy
NCT00494039
125
NCT00331773
RT in treating patients with stage II PCa Profit: prostate fractionated irradiation trial RT In treating patients with stage II PCa ADT and RT in treating patients with PCa
NCT00304759 NCT00033631 NCT01368588
NCT01272050 NCT01839994
NCT00967863
I vs
103
Pd brachytherapy
RT in treating patients with relapsed PCa after surgery Conformal RT alone vs conformal RT combined with HDR brachytherapy or SBRT for PCa RT in treating patients receiving ADT for PCa
Recruiting Recruiting Recruiting
Recruiting
Hypofractionation via extended vs accelerated RT
NCT00175396
Completed
Recruiting
NCT01794403
NCT01444820
Recruiting
Active surveillance vs RP vs EBRT vs brachytherapy RP vs RT
Side effect reduction through IMRT compared to 3D-conformal RT Accelerated hypofractionated regimen will not be inferior to the standard treatment An increased dose to the MRI-defined lesion in the prostate bed will result in better initial CR Compare hypofractionation to standard proton RT HDR boost will achieve better PFS compared to LDR with a better toxicity profile and QoL Erectile dysfunction rate reduction when restricting the dose to erectile tissue Safety and reduction of toxicity using the SpaceOAR system Is hypofractionated IMRT as good or better than conventional RT Safety evaluation of dose-escalated hypofractionated RT Is a brachytherapy boost better than an EBRT boost Evaluation of whether fewer side effects occur for proton therapy compared to EBRT Brachytherapy better with or without EBRT for intermediate-risk PCa A 10% reduction in applied dose could reduce side effects while still being adequate The shorter half-life of 103Pd vs 125I will increase the rate of tumor eradication Comparison of different RT regimens, hypofractionation results Evaluation of hypofractionation results Compares the effectiveness of two different IMRT doses Better overall survival OS When the RT Volume Is Increased On The Whole Pelvis Comparison of two salvage doses for biochemically recurrent PCa Outcome comparison
NCT01936883
Status
Not yet recruiting
Recruiting
Recruiting
Recruiting Not yet recruiting
Active, not recruiting
Active, not recruiting Active, not recruiting Recruiting Active, not recruiting Recruiting
Active, not recruiting Recruiting
Active, not recruiting
Active, not recruiting Active, not recruiting Active, not recruiting Recruiting
Active, not recruiting Not yet recruiting
Recruiting
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
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Table 3 (Continued ) ClinicalTrials.gov
Short name
Start date (D/M/Y)
Planned accrual
FLAME: investigate the benefit of a focal lesion ablative microboost in PCa Triptorelin and RT after surgery for intermediate-risk stage III or IV PCa
9/9/2014
566
12/1/2007
718
10/1/2002
2163
NCT00860652
IMRT in treating patients with localized PCa Trial to evaluate RT followed by ADT vs ADT alone for PSA failure after RP Adjuvant vs early salvage RT
NCT01550237
Curative image-guided RT for PCa
NCT01168479
NCT00667069
NCT00392535 NCT00138008
5/1/2004
200
3/1/2009
470
1/10/2012
260
Question addressed SIB to the focal lesion could produce better results without increased toxicity Compare the results of ADT + RT immediately after surgery vs delaying treatment Comparison of the side effects of three IMRT schedules Comparison of RT with ADT to ADT alone after biochemical recurrence Comparing adjuvant vs early salvage RT in PCa with positive margins or extraprostatic disease following RP Investigate whether cone beam IGRT and consequently reduced safety margins can reduce rectal side effects
Status Recruiting
Recruiting
Recruiting Recruiting
Recruiting
Recruiting
PCa = prostate cancer; RP = radical prostatectomy; RARP = robot-assisted RP; PEEP = positive end expiratory pressure; RT = radiotherapy; SBRT = stereotactic body RT, IMRT = intensity-modulated RT; IGRT = image-guided RT; EBRT = external beam RT; HDR = high dose rate; LDR = low dose rate; SIB = simultaneous integrated boost; ADT = androgen deprivation therapy; PSA = prostate-specific antigen; MRI = magnetic resonance imaging; NA = neoadjuvant; CR = complete response; QoL = quality of life.
Table 4 – Trials investigating both local and systemic treatments (n = 11, total expected accrual 19 822) ClinicalTrials.gov
Short name
Start date (D/M/Y)
Planned accrual
NCT01546623
Comparative study of TAP-144-SR in PCa patients previously treated with ADT
3/1/2012
164
NCT02044172
ProtecT trial: prostate testing for cancer and treatment Single-dose local RT compared with ibandronate in treating patients with localized metastatic bone pain
6/1/2001
1500
4/3/2014
580
Cabazitaxel and pelvic RT in localized PCa and high-risk features of relapse STAMPEDE trial: systemic therapy in advancing or metastatic PCa: evaluation of drug efficacy RT with or without bicalutamide and goserelin in treating patients with PCa Study on the role of hormonal treatment for two dosage levels of prostate RT vs prostate RT alone A phase 3 trial of ADT local RT abiraterone in metastatic hormonenaı¨ve PCa Prostate RT or short-term ADT and pelvic lymph node RT with or without prostate RT in treating patients with rising PSA after surgery for PCa RADICALS: RT And ADT in treating patients who have undergone surgery for PCa Surgery with or without docetaxel and leuprolide or goserelin for highrisk localized PCa
9/13/2014
1048
9/5/2014
8100
5/1/2003
400
12/1/2000
600
10/1/2013
916
NCT00082927
NCT01952223
NCT00268476
NCT00067015
NCT00223145
NCT01957436
NCT00567580
NCT00541047
NCT00430183
2/1/2008
1764
10/1/2007
4000
12/1/2006
750
Question addressed
Hormone dynamics, pharmacokinetics, safety and efficacy of TAP-144-SR for 6 mo vs 3 mo Active surveillance vs RP vs RT plus ADT Comparing pain response of ibandronate vs single-dose local RT with 8 Gy in treating patients with localized metastatic bone pain Assess the effect on clinical PFS of NA cabazitaxel and pelvic RT with ADT vs prostate-only RT with ADT Assessment of 5 treatments usually held for CRPC used sooner in combination with ADT Comparing QoL of high-dose IMRT to 86.4 Gy alone vs IMRT To 75.6 Gy plus NA/adjuvant ADT Would adding 6 mo of ADT lead to local failure reduction when using 70 or 76 Gy vs 76 Gy alone Compare the clinical benefit of ADT local RT abiraterone acetate and prednisone in metastatic PCa Comparing prostate RT to shortterm ADT with pelvic lymph node RT prostate RT in biochemically recurrent PCa RT timing (adjuvant vs early salvage) and ADT duration after local surgery Comparing NA docetaxel and ADT vs surgery alone in patients with high-risk localized PCa
Status
Recruiting
Active, not recruiting Completed
Recruiting
Recruiting
Completed
Active, not recruiting
Not yet recruiting
Recruiting
Recruiting
Recruiting
PCa = prostate cancer; RT = radiotherapy; IMRT = intensity-modulated radiotherapy; RP = radical prostatectomy; CRPC = castration-resistant PCa; ADT = androgen deprivation therapy; PSA = prostate-specific antigen; PFS = progression-free survival; NA = neoadjuvant; QoL = quality of life.
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
EUF-34; No. of Pages 12 EUROPEAN UROLOGY FOCUS XXX (2015) XXX–XXX
11
Fig. 3 – Circle diagram characterizing the trials identified.
these advances in clinical trials. Surprisingly, the heavily debated topic of focal therapy is being analyzed in just two phase 3 randomized clinical trials that we identified, NCT01168479 (one of the seven uncategorized trials) and NCT01310894. An additional search in the original database of 2951 prostate trials identified revealed more than 30 phase 1 and phase 2 trials on focal therapy that are ongoing or completed. This supports the previously expressed concern that focal therapy remains in its infancy and should thus only be regarded as an experimental approach [7]. Technological advances in robotics and its application in localized disease have not yet been verified in phase 3 randomized clinical trials. Only two trials directly compared surgery to radiation therapy, the ProtecT trial (NCT02044172) and the PREFERE trial (NCT01717677).
Our analysis is not without limitations. Not every clinical trial is registered on ClinicalTrials.gov; registration is obligatory for all US studies, but not for non-US trials. Therefore, possible selection bias regarding our findings for trial locations is possible. Nevertheless, as ClinicalTrials.gov is the largest global trials registry database available, with 52% of all registered trials non–US-based, our findings provide a representative, if not complete, picture of current research in prostate cancer. Some trials might have been incorrectly registered in the ClinicalTrials.gov registry. Moreover, we cannot exclude the possibility of errors whereby certain trials were not captured for the analysis and/or were misclassified during the selection process. In addition, the data sets for all trials in the database are not always complete and up to date. However, we took great care to minimize these limitations: two authors
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
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EUROPEAN UROLOGY FOCUS XXX (2015) XXX–XXX
(A.T. and P.G.) crosschecked all trials identified and the trial selection steps. We believe that our analysis is unique and important, and that the comprehensive tables provide researchers and clinicians with a realistic picture of the future of prostate cancer treatment. 5.
Conclusions
Our analysis demonstrates strong ongoing clinical research activity that will undoubtedly impact on the future of prostate cancer treatment worldwide. Most of the phase 3 trials with pending results address questions regarding systemic treatments for both nonmetastatic and metastatic disease. In the subgroup of trials testing local treatments, radiation therapy is the focus of the majority of investigations and shows the greatest potential for further improvement.
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: None. Funding/Support and role of the sponsor: None.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. euf.2015.05.003.
References [1] Hirsch BR, Califf RM, Cheng SK, et al. Characteristics of oncology clinical trials: insights from a systematic analysis of ClinicalTrials. gov. JAMA Intern Med 2013;173:972–9.
Author contributions: Pirus Ghadjar had full access to all the data in the
[2] Fizazi K, Abrahamsson PA, Ahlgren G, et al. Achievements and
study and takes responsibility for the integrity of the data and the
perspectives in prostate cancer phase 3 trials from genitourinary
accuracy of the data analysis.
research groups in Europe: introducing the Prostate Cancer Consortium in Europe. Eur Urol 2015;67:904–12.
Study concept and design: Tsikkinis, Budach, Wust, Cihoric, Giannarini,
[3] Scher HI, Halabi S, Tannock I, et al., Prostate Cancer Clinical Trials
Ghadjar.
Working Group. Design and end points of clinical trials for patients
Acquisition of data: Tsikkinis, Cihoric, Ghadjar, Giannarini.
with progressive prostate cancer and castrate levels of testoster-
Analysis and interpretation of data: All authors.
one: recommendations of the Prostate Cancer Clinical Trials Work-
Drafting of the manuscript: Tsikkinis, Ghadjar.
ing Group. J Clin Oncol 2008;26:1148–59.
Critical revision of the manuscript for important intellectual content: All authors.
[4] Schwartz LM, Woloshin S, Fowler Jr FJ, Welch HG. Enthusiasm for cancer screening in the United States. JAMA 2004;291:71–8.
Statistical analysis: None.
[5] Schro¨der FH, Hugosson J, Roobol MJ, et al. Screening and prostate
Obtaining funding: None.
cancer mortality: results of the European Randomised Study of
Administrative, technical, or material support: None.
Screening for Prostate Cancer (ERSPC) at 13 years of follow-up.
Supervision: Giannarini.
Lancet 2014;384:2027–35.
Other: None. Acknowledgements: We would like to thank Branislav Trninic and Tomislav Cuk from KapitalSoft - Trebinje for technical support and advices for data processing.
[6] Kuban DA, Levy LB, Cheung MR, et al. Long-term failure patterns and survival in a randomized dose-escalation trial for prostate cancer. Who dies of disease? Int J Radiat Oncol Biol Phys 2011;79: 1310–7. [7] Giannarini G, Gandaglia G, Montorsi F, Briganti A. Will focal therapy
Financial disclosures: Pirus Ghadjar certifies that all conflicts of interest,
remain only an attractive illusion for the primary treatment of
including specific financial interests and relationships and affiliations
prostate cancer? J Clin Oncol 2014;32:1299–301.
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Prostate Cancer
Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database Alexandros Tsikkinis a, Nikola Cihoric a, Gianluca Giannarini b, Stefan Hinz c, Alberto Briganti d, Peter Wust e, Piet Ost f, Guillaume Ploussard g, Christophe Massard h, Cristian I. Surcel i, Prasanna Sooriakumaran j, Hendrik Isbarn k, Peter J.L. De Visschere l, Jurgen J. Futterer m, Roderick C.N. van der Bergh n, Alan Dal Pra a, Daniel M. Aebersold a, Volker Budach e, Pirus Ghadjar e,* a
Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland; b Department of Urology, University of
Udine, Udine, Italy;
c
Department of Urology, Charite´ Universita¨tsmedizin Berlin, Berlin, Germany;
d
Unit of Urology/Division of Oncology, Ospedale
San Raffaele, Milan, Italy; e Department of Radiation Oncology, Charite´ Universita¨tsmedizin Berlin, Berlin, Germany; f Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, Ghent, Belgium; g Department of Urology, Saint-Louis Hospital, Paris, France;
h
Institut Gustave
Roussy, University of Paris Sud, Villejuif, France; i Centre of Urological Surgery, Dialysis and Renal Transplantation, Fundeni Clinical Institute, Bucharest, Romania; j Surgical Intervention Trials Unit, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; k Regio Clinicum Wedel, Department of Urology and Martini-Clinic, Prostate Cancer Center, Hamburg-Eppendorf, Germany; l Department of Radiology, Division of Genitourinary Radiology, Ghent University Hospital, Ghent, Belgium; m Department of Radiology, Radboud University, Nijmegen Medical Centre, Nijmegen, The Netherlands; n Department of Urology, University Medical Centre Utrecht, Utrecht, The Netherlands
Article info
Abstract
Article history: Accepted May 5, 2015
Background: It is not easy to overview pending phase 3 trials on prostate cancer (PCa), and awareness of these trials would benefit clinicians. Objective: To identify all phase 3 trials on PCa registered in the ClinicalTrials.gov database with pending results. Design and setting: On September 29, 2014, a database was established from the records for 175 538 clinical trials registered on ClinicalTrials.gov. A search of this database for the substring ‘‘prostat’’ identified 2951 prostate trials. Phase 3 trials accounted for 441 studies, of which 333 concerned only PCa. We selected only ongoing or completed trials with pending results, that is, for which the primary endpoint had not been published in a peer-reviewed medical journal. Results and limitations: We identified 123 phase 3 trials with pending results. Trials were conducted predominantly in North America (n = 63; 51%) and Europe (n = 47; 38%). The majority were on nonmetastatic disease (n = 82; 67%), with 37 (30%) on metastatic disease and four trials (3%) including both. In terms of intervention, systemic treatment was most commonly tested (n = 71; 58%), followed by local treatment 34 (28%), and both systemic and local treatment (n = 11; 9%), with seven (6%) trials not classifiable. The 71 trials on systemic treatment included androgen deprivation therapy (n = 34; 48%), chemotherapy (n = 15; 21%), immunotherapy (n = 9; 13%), other systemic drugs (n = 9; 13%), radiopharmaceuticals (n = 2; 3%), and combinations (n = 2; 3%). Local treatments tested included radiation therapy (n = 27; 79%), surgery (n = 5; 15%), and both (n = 2; 2%). A limitation is that not every clinical trial is registered on ClinicalTrials.gov. Conclusion: There are many PCa phase 3 trials with pending results, most of which address questions regarding systemic treatments for both nonmetastatic and metastatic
Associate Editor: James Catto Keywords: Prostate cancer Trials ClinicalTrials.gov Prospective
* Corresponding author. Department of Radiation Oncology, Charite´ Universita¨tsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. Tel. +49 30 450 657055; Fax: +49 30 450 7527152. E-mail address: [email protected] (P. Ghadjar). http://dx.doi.org/10.1016/j.euf.2015.05.003 2405-4569/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
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disease. Radiation therapy and androgen deprivation therapy are the interventions most commonly tested for local and systemic treatment, respectively. Patient summary: This report describes all phase 3 trials on prostate cancer registered in the ClinicalTrials.gov database with pending results. Most of these trials address questions regarding systemic treatments for both nonmetastatic and metastatic disease. Radiation therapy and androgen deprivation therapy are the interventions most commonly tested for local and systemic treatment, respectively. # 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
1.
Introduction
trials were still considered as having pending results and included in the analysis.
Changes in clinical practice are commonly driven by results from randomized phase 3 trials. While published trial results are summarized by guideline recommendations and textbooks with a certain time delay, it is less easy to overview phase 3 trials that have not yet reported their primary endpoint(s), that is, ongoing trials or trials that have completed accrual but need additional follow-up time for data maturity and manuscript development and publication. Awareness of these pending trials could help avoid duplication of trials and a waste of scarce resources. It might also provide clinicians with an idea of important questions to be answered in the near future and questions that have not yet been asked, and at the same time acknowledge which phase 3 trials have failed and the reasons that led to such failure. To the best of our knowledge, this is the most comprehensive assessment of ongoing phase 3 research in prostate cancer. ClinicalTrials.gov is the most robust of the international public clinical trial registries and has already proven useful for systematic analyses [1]. Completed and ongoing European phase 3 trials on prostate cancer have recently been reviewed according to expert opinion [2]. In the present study we attempt to build on these results using a worldwide approach that involves a systematic analysis of the ClinicalTrials.gov database. 2.
Materials and methods
The records for 175 538 clinical trials registered on ClinicalTrials.gov were downloaded on September 29, 2014 and a database was established. We searched this database for the substring ‘‘prostat’’. In total, 2951 prostate trials were identified. Phase 3 trials accounted for 441 studies, of which 333 concerned only prostate cancer. Trials covering multiple tumor entities, as well as prostate cancer prevention trials, were excluded. We then identified (1) trials that were active but not yet recruiting; (2) trials that were active and recruiting; and (3) trials that had been completed for which the primary endpoint had not been objectively published in a peer-reviewed medical journal (Fig. 1). This process was achieved via manual crosschecking on with www.pubmed.org by searching for English peer-reviewed original publications describing results for the primary trial endpoint using appropriate follow-up duration and sample size. Completed trials for which accrual had finished >10 yr previously were excluded, as it was assumed that results for these trials will never be published. In addition, the Internet was browsed for conference abstracts and the ClinicalTrials.gov registry was searched for uploaded references or trial results for the primary trial endpoint. If a conference abstract was found or trial results were available within the registry, but no peerreviewed original publication was identified, this was noted and such
The location in which each trial was conducted was noted from the ClinicalTrials.gov database according to the location of the principal investigator or the corporate headquarters of the leading sponsor agency. Trials were also grouped according to the primary intervention (systemic vs local vs both systemic and local treatments) and disease stage (metastatic vs nonmetastatic disease). Trials testing local treatments (radiation therapy, surgery, or a combination of the two) were subclassified according to patient risk profile (low-risk vs intermediaterisk vs high-risk). All trials were then further subclassified according to clinical states model recommended by the Prostate Cancer Clinical Trials Working Group (PCWG2). The clinical states model categorizes the disease continuum and allows more detailed characterization of prostate cancer patients according to five different groups. This was done to provide readers with an overview of the different disease states investigated in the trials (Supplementary Table 1) [3].
3.
Results
We identified 123 phase 3 trials with pending results. The trial characteristics are summarized in Table 1. Results concerning the primary trial endpoint have been presented in abstract form for seven of these trials. The trials were predominantly performed in North America (n = 63; 51%). More than one third of trials were carried out in each of the USA (n = 50; 41%) and Europe (n = 47; 38%). France (n = 14; 11%) and Switzerland (n = 6; 5%) together accounted for almost half of all European trials. Only nine trials were conducted in Asia (7%) and four in Australia (3%) (Fig. 2). Industry funding was almost exclusively for systemic treatments (31 trials). By contrast, industry funding was provided for just one trial investigating radiation therapy and no surgery trials. There was a more even distribution of funding by universities, hospitals, and research groups and agencies (79 trials), with funding for 44 trials investigating systemic therapies and 38 trials assessing local therapies. The 123 trials were supported by 82 individual sponsors. The Radiation Therapy Oncology Group (RTOG) sponsored the greatest number of trials (n = 10; 8%), followed by the privately funded French Unicancer Group (n = 7; 6%). The majority of trials were conducted for patients with nonmetastatic disease (n = 82, 67%), followed by patients with metastatic disease (n = 37, 30%). The remaining four trials (3%) tested both metastatic and nonmetastatic disease. Among the 123 trials, 71 (58%) tested some form of systemic treatment (Table 2), 34 (28%) tested local
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
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EUROPEAN UROLOGY FOCUS XXX (2015) XXX–XXX
Complete ClinicalTrials.gov database n = 175 538
29.09.14
Trial identification using the substring "prostat" within the subset "Conditions"
All prostate-related trials n = 2 951
Prostate "phase 3" trial identification
All phase 3 prostate trials n = 441
Prostate "cancer" trial identification
Excluded
Other non–cancer-related prostate trials or multiple tumor entities
n = 108
All phase 3 Prostate cancer trials n = 333
02.11.14
Manual categorization
Excluded
Excluded
Terminated/suspended/nonrandomized trials with primary endpoint/s not published
Completed trials with published primary endpoint/s n = 141
Randomized phase 3 trials with primary endpoint/s not published
n = 69
n = 123
Fig. 1 – Flow diagram of the database search.
treatment (Table 3), and 11 (9%) tested both systemic and local treatments (Table 4). The disease state according to PCWG2 recommendations is listed for treatment interventions in Supplementary Table 1. In total, 101 882 patients
were expected to be randomized, with more than half of these randomized in trials testing systemic therapies (n = 54 754; 54%). Trials testing local treatments accounted for 27% of all patients (n = 27 306) and the remaining
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
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EUROPEAN UROLOGY FOCUS XXX (2015) XXX–XXX
Table 1 – Trial characteristics
a
Trial attribute
Trials, n (%) All (n = 123)
Lead sponsor Industry University Hospital or center Group or agency Other Masking Open Single blind Double blind NA Number of arms 1 2 3 4 NA Enrollment 0–100 101–500 501–1000 >1000 Location North America Europe Asia Oceania a
Systemic therapy (n = 82)
Radiation therapy (n = 39)
Surgery (n = 9)
Others (n = 7)
32 20 25 34 12
(26) (16) (20) (28) (10)
31 11 11 22 7
1 5 11 15 7
0 3 1 4 1
0 3 0 3 1
83 6 26 8
(67) (5) (21) (7)
50 1 24 7
35 3 0 1
7 2 0 0
5 0 2 0
2 94 7 7 13
(2) (76) (6) (6) (10)
2 59 7 5 9
0 28 3 4 4
0 7 1 1 0
0 4 0 1 2
9 54 30 31
(7) (44) (24) (25)
5 32 22 23
3 16 8 12
1 3 1 4
0 5 2 0
63 47 9 4
(51) (28) (7) (3)
39 33 8 2
22 15 1 1
4 5 0 0
3 3 0 1
Some trials included more than one intervention, so the number of trials summed for interventions may be greater than the total number of trials.
19% were randomized in trials testing both systemic and local treatments (n = 19,822). Radiation therapy was tested alone or as a component in 39 (32%) trials. The majority of these 39 trials used intensity-modulated radiation therapy (n = 27; 69%); seven
(18%) trials investigated hypofractionated treatment schedules (data not shown). Surgery was a component in nine (7%) trials. Seven trials (n = 7; 6%) tested miscellaneous activities that could not be assigned to any specific category (Table 1, Fig. 3).
Fig. 2 – Heat map describing the locations where trials were conducted. An interactive version of the map can be accessed at http://jsfiddle.net/ pvpnz41o/6/embedded/result/.
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
EUF-34; No. of Pages 12 5
EUROPEAN UROLOGY FOCUS XXX (2015) XXX–XXX
Table 2 – Trials investigating systemic treatments (n = 71; total accrual expected 54 754) ClinicalTrials.gov
Short name
Chemotherapy (n = 15; 7316 patients) Patient preference between NCT02044354 cabazitaxel and docetaxel in MCRPC NCT00796458 NCT00436839 NCT01522443
NCT00764166
ADT with or without docetaxel for advanced PCa Taxotere PCa new indication registration trial in China Cabozantinib (XL184) vs mitoxantrone + prednisone in men with previously treated symptomatic CRPC Prospective randomized phase 3 study comparing ADT docetaxel
Start date (D/M/Y)
Planned accrual
1/1/2014
174
4/5/2014
200
1/1/2007
228
3/1/2012
246
6/1/2003
254
NCT00132301
Chemotherapy after prostatectomy (CAP) for high-risk PCa
6/1/2006
298
NCT00116142
ADT and RT for 6 mo docetaxel for high-risk PCa
6/1/2005
350
NCT00653848
Treatment of PCa with docetaxel + ADT vs ADT alone in patients treated with RP Docetaxel compared with observation in treating patients who have undergone RP for PCa Efficacy study evaluating chemotherapy In PCa
5/1/2007
378
10/1/2005
396
11/12/2014
400
ADT + RT or ADT + RT followed by docetaxel and prednisone in treating patients with localized PCa Comparison of cabazitaxel/ prednisone alone or with custirsen for second-line chemotherapy in PCa CHAARTED: chemohormonal therapy vs ADT randomized trial for extensive disease in PCa Cabazitaxel vs docetaxel both with prednisone in patients with MCRPC
12/1/2005
612
8/12/2014
630
7/1/2006
780
5/1/2011
1170
Cabazitaxel 20 mg/m2 compared to 25 mg/m2 with prednisone for the treatment of MCRPC ADT (n = 34; 35 604 patients) NCT00553878 Comparing 0.5 mg dutasteride vs placebo daily in men receiving ADT for PCa
4/11/2014
1200
NCT00376792
NCT01978873
NCT00288080
NCT01578655
NCT00309985
NCT01308567
NCT01308580
3/1/2007
100
NCT01398657
Cryotherapy with or without shortterm adjuvant ADT in PCa
7/1/2011
182
NCT01492972
Hypofractionated proton RT with or without ADT for intermediate-risk PCa Study of abiraterone acetate plus prednisone in MCRPC patients after failed docetaxel chemotherapy
1/1/2012
192
8/12/2014
214
Study to compare the effect of ASP3550 with goserelin in patients with PCa Effect of Enantone LP 11.25 mg (leuprorelin) on histologic progression of indolent PCa
8/13/2014
230
3/1/2013
240
NCT01695135
NCT01964170
NCT02085252
Question addressed
Evaluate patient preference between cabazitaxel and docetaxel in first-line chemotherapy for MCRPC Evaluate BPFS for ADT + docetaxel vs ADT alone in advanced PCa Compare docetaxel + prednisone vs mitoxantrone + prednisone in MCRPC Compare pain and bone scan responses for cabozantinib vs mitoxantrone + prednisone in CRPC Evaluate PFS of high-risk metastasisfree PCa in patients treated with ADT for 1 yr docetaxel after prior RP or RT Evaluate efficacy of early adjuvant chemotherapy for PCa potentially cured by RP but at high risk of relapse Determine if there is an OS benefit when adding docetaxel to ADT and RT for high-risk PCa Effectiveness of adjuvant docetaxel after RT to prevent early relapse in intermediate- and high-risk PCa Compare BPFS for docetaxel vs surveillance after RP with positive margins Is there a benefit of adding cabazitaxel before ADT vs ADT alone in metastatic or high-risk PCa Compare OS for ADT and RT followed by docetaxel and prednisone vs ADT and RT alone for localized PCa Addition of custirsen to cabazitaxel/ prednisone slows tumor progression and enhances OS vs cabazitaxel/ prednisone alone in MCRPC ADT with or without chemotherapy in treating patients with metastatic PCa Improved OS with cabazitaxel + prednisone vs docetaxel + prednisone in chemo-naive MCRPC OS noninferiority of cabazitaxel 20 mg/m2 vs 25 mg/m2 in docetaxeltreated MCRPC Daily dutasteride 0.5 mg could increase the off-treatment interval in men under intermittent ADT for localized PCa Compare PFS for cryoablation alone vs cryoablation plus ADT in high-risk localized PCa Examine the benefit of adding ADT To hypofractionated proton RT vs proton RT alone with regard to failure Evaluate safety and BPFS efficacy of abiraterone acetate plus prednisone in Asian MCRPC patients after failed docetaxel-based chemotherapy Compare the safety and efficacy of degarelix vs goserelin in patients with PCa Assess leuprorelin vs active surveillance without ADT for indolent PCa and compare their therapeutic benefit for low-risk localized PCa
Status
Recruiting
Recruiting Completed Active, not recruiting
Active, not recruiting
Active, not recruiting
Recruiting
Recruiting
Recruiting
Recruiting
Active, not recruiting
Recruiting
Recruiting
Active, not recruiting
Active, not recruiting
Active, not recruiting
Recruiting
Recruiting
Active, not recruiting
Active, not recruiting
Recruiting
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
EUF-34; No. of Pages 12 6
EUROPEAN UROLOGY FOCUS XXX (2015) XXX–XXX
Table 2 (Continued ) ClinicalTrials.gov
Short name
Start date (D/M/Y)
Planned accrual
Question addressed
Status
Compare the efficacy and safety of degarelix for 1 mo vs goserelin in Chinese patients with PCa requiring ADT Compare BPFS for abiraterone acetate plus prednisone vs placebo in MCRPC
Active, not recruiting
Evaluate the potential additional impact on BPFS of 2 yr of ADT with goserelin vs goserelin for 4 mo plus daily bicalutamide for 2 mo for highrisk PCa Investigate the safety and BPFS efficacy of intermittent vs continuous degarelix for PCa with prior treatment failure after localized treatment Study whether additional adjuvant GnRH agonist therapy improves BPFS
Active, not recruiting
NCT01744366
1-mo degarelix/comparator treatment for PCa in a Chinese population
1/1/2013
280
NCT01591122
Study of abiraterone acetate plus prednisone in patients with chemonaive MCRPC Trial of adjuvant ADT in combination with 3D-conformal RT doses in high- and intermediaterisk localized PCa.
3/1/2012
313
11/5/2014
358
NCT00928434
Study of degarelix in patients with PCa
5/1/2009
405
NCT00664456
Neoadjuvant GnRH agonist therapy and permanent 125I implants adjuvant GnRH agonist therapy in previously untreated intermediaterisk PCa Triptorelin, flutamide, and EBRT or EBRT alone in treating stage II or III PCa RT with or without goserelin for patients who have undergone surgery for recurrent or refractory PCa ADT in treating patients with stage I or II PCa
4/8/2014
420
7/1/2004
450
Studying the efficacy of NA ADT with EBRT vs EBRT alone
Recruiting
10/1/2006
466
Compare OS for adjuvant RT with ADT vs without ADT in recurrent or refractory PCa
Recruiting
6/1/1999
496
Determine the effectiveness of ADT for 1 yr vs no ADT for PCa at high risk of recurrence after RP OS comparison of ADT withdrawal vs maintenance and intermittent vs continuous chemotherapy in CRPC Compare survival for 18 mo vs 36 mo of ADT combined with pelvic RT in high-risk PCa Compare BPFS for intermittent vs continuous ADT in relapsing and locally advanced PCa Compare the BPFS effectiveness of RT with ADT vs without ADT in localized PCa Compare OS for RT with ADT vs without in stage II,III, or biochemically recurrent PCa after RP Compare the efficacy and safety of 3mo degarelix dosing regimen vs goserelin acetate Compare OS for dose-escalated RT and standard ADT (GnRH agonist) vs enhanced ADT (GnRH agonist+TAK700) Compare OS for orteronel + prednisone vs placebo + prednisone in MCRPC Comparing Time To Androgen Independent Disease Of Immediate Vs Deferred ADT For Recurrent PCa After RP Compare OS for Abiraterone acetate plus low-dose prednisone plus ADT vs ADT alone in MCRPC Evaluate the efficacy and safety of ARN-509 vs placebo in high-risk nonMCRPC Compare OS for enzalutamide alone vs enzalutamide, abiraterone acetate and prednisone in MCRPC
Active, not recruiting
NCT02175212
NCT00104741
NCT00423475
NCT00003645
NCT01224405
PCa ADT withdrawal and intermittent chemotherapy
4/10/2014
600
NCT00223171
Duration of ADT combined with pelvic RT in PCa
10/1/2000
650
NCT00378690
Phase 3b study of intermittent vs continuous ADT with ELIGARD
3/1/2006
706
NCT00021450
RT with or without bicalutamide and goserelin in treating patients with PCa RT with or without bicalutamide in treating patients with stage II, III, or recurrent PCa A trial of degarelix in patients with PCa
4/1/2014
800
2/1/1998
840
6/1/2009
859
900
NCT00002874
NCT00946920
NCT01546987
ADT, RT, and steroid 17-amonooxygenase TAK-700 in treating high-risk PCa
5/1/2012
NCT01193257
Study comparing orteronel plus prednisone in patients with MCRPC
11/10/2014
1099
NCT00439751
Immediate vs deferred ADT for recurrent PCa after radical RT
4/7/2014
1100
NCT01715285
Study of abiraterone acetate plus low-dose prednisone plus ADT vs ADT alone for MCRPC Study of ARN-509 in men with nonMCRPC
2/1/2013
1200
9/13/2014
1200
1/1/2014
1224
NCT01946204
NCT01949337
Enzalutamide with or without abiraterone acetate and prednisone in treating patients with MCRPC
Active, not recruiting
Completed
Active, not recruiting
Active, not recruiting
Active, not recruiting
Completed
Active, not recruiting
Active, not recruiting
Completed
Recruiting
Completed
Active, not recruiting
Recruiting
Recruiting
Recruiting
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
EUF-34; No. of Pages 12 7
EUROPEAN UROLOGY FOCUS XXX (2015) XXX–XXX
Table 2 (Continued ) ClinicalTrials.gov NCT01193244
NCT01809691
NCT02200614
NCT00936390 NCT02003924
NCT00005044
NCT00110162
Short name
NCT02111577
Question addressed
Status
Evaluate PFS and OS for orteronel + prednisone vs placebo + prednisone in MCRPC Compare OS in metastatic PCa randomly assigned to ADT plus orteronel vs ADT plus bicalutamide Comparing metastasis-free survival for OMD-201 vs placebo in high-risk non-MCRPC Compare OS for RT with ADT for 6 mo vs without ADT Compare metastasis-free survival for enzalutamide vs placebo in nonMCRPC Disease-specific survival for ADT for 8 wk vs 28 wk followed by RT with concurrent ADT in intermediate-risk PCa Compare the timing of intervention with ADT in PCa with rising Evaluating metastasis-free survival for 24-mo adjuvant ADT vs surveillance after RP
Active, not recruiting
10/1/2010
1454
3/1/2013
1486
Efficacy and safety study of ODM201 in men with high-risk nonMCRPC RT with or without ADT in treating patients with PCa Safety and efficacy study of enzalutamide in patients with nonMCRPC ADT And RT in treating patients with PCa
9/14/2014
1500
9/9/2014
1520
12/1/2013
1560
2/1/2000
1579
10/1/2004
2000
1/6/2011
700
5/1/2010
600
9/11/2014
711
11/9/2014
760
6/1/2012
960
ADT in treating patients with PCa
Benefit evaluation of adjuvant ADT for 24 mo after RP in patients with high risk of recurrence Immunotherapy (n = 9; 8281 patients) Phase 3 study of immunotherapy to NCT01057810 treat advanced PCa Study of ProstAtak immunotherapy NCT01436968 with standard RT for localized PCa
NCT01605227
Planned accrual
Study comparing orteronel plus prednisone in patients with chemotherapy-naive MCRPC S1216, ADT + orteronel vs ADT + bicalutamide for metastatic PCa
NCT01442246
NCT00925600
Start date (D/M/Y)
Compare lens opacification in nonmetastatic PCa receiving denosumab for bone loss due to ADT Study of cabozantinib (XL184) vs prednisone in men with MCRPC previously treated with docetaxel and abiraterone or MDV3100 Study of DCVAC added to standard chemotherapy for men with MCRPC
4/14/2014
1170
NCT01234311
A study of tasquinimod in men with MCRPC
3/1/2011
1200
NCT02057666
Study of tasquinimod in Asian chemo-naive patients with MCRPC
1/1/2014
300
Efficacy trial of PROSTVAC-V/F GM-CSF in men with asymptomatic or minimally symptomatic MCRPC Prevention of symptomatic skeletal NCT02051218 events with denosumab administered every 4 wk vs 12 wk Radiopharmaceuticals (n = 2; 825 patients) NCT00024167 Chemotherapy with or without strontium-89 in treating patients with PCa Phase 3 radium-223 MCRPC-PEACE NCT02194842 3 Trial NCT01322490
Other systemic drugs (n = 9; 1808 patients) GTN therapy on biomarkers of NCT01704274 immune escape in men with biochemical recurrence of PCa Zoledronic acid for the prevention NCT00058188 of bone loss in men with PCa on long-term ADT NCT01006395
Prevention of microarchitectural bone decay in males with nonmetastatic PCa receiving ADT
11/11/2014
1200
7/1/2014
1380
4/2/2014
265
12/1/2014
560
4/12/2014
60
3/1/2003
70
1/1/2011
100
Compare OS for ipilimumab vs placebo in MCRPC Evaluate the effectiveness of ProstAtak immunotherapy + RT vs placebo + RT for localized PCa Compare lens opacification in nonmetastatic PCa receiving denosumab for bone loss due to ADT vs placebo Evaluate the effect of cabozantinib vs prednisone on OS in men with previously treated MCRPC Evaluate the OS efficacy and safety of DCVAC with standard chemotherapy vs placebo in MCRPC Confirm the effect of tasquinimod on delaying disease progression compared with placebo in MCRPC Confirm the effect of tasquinimod in delaying disease progression or death vs placebo in chemo-naive MCRPC Determine whether PROSTVAC alone or combined with GM-CSF can prolong OS in MCRPC Test if the benefit of denosumab is maintained if administered every 12 wk vs every 4 wk
Recruiting
Recruiting
Recruiting Recruiting
Active, not recruiting
Recruiting Active, not recruiting
Active, not recruiting Recruiting
Recruiting
Active, not recruiting
Recruiting
Active, not recruiting
Recruiting
Recruiting
Recruiting
Compare OS for chemotherapy with strontium-89 vs chemotherapy alone for bone-metastasized PCa Compare PFS for enzalutamide vs a combination of radium 223 and enzalutamide in MCRPC
Completed
Effect of transdermal GTN on biomarkers of immune escape in biochemically recurrent PCa Comparing the effectiveness of zoledronic acid combined with calcium vs calcium alone in preventing bone loss Compare bone microarchitectural changes when administering zoledronic acid vs placebo
Recruiting
Not yet recruiting
Active, not recruiting
Recruiting
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
EUF-34; No. of Pages 12 8
EUROPEAN UROLOGY FOCUS XXX (2015) XXX–XXX
Table 2 (Continued ) ClinicalTrials.gov NCT00887432
NCT00426777
NCT00685646
NCT01864096
Short name Cholecalciferol supplement in treating patients with localized PCa undergoing observation Efficacy study of risedronate to prevent cancer treatment–induced bone loss in PCa ADT with or without zoledronic acid in treating patients with PCa and bone metastases Metformin Active Surveillance Trial (MAST) Study
NCT02220829
Comparative study of use of alphablockers to treat symptoms in PCa patients undergoing RT Study of zoledronic acid for patients NCT00242567 with hormone-sensitive bone metastases from PCa Combinations (n = 2; 920 patients) EBRT concurrent with docetaxel NCT01811810 and adjuvant short-course ADT NCT02043678
Radium-223 dichloride and abiraterone acetate compared to placebo and abiraterone acetate for PCa
Start date (D/M/Y)
Planned accrual
12/1/2009
100
1/1/2007
160
5/1/2008
200
10/1/2013
408
10/1/2014
188
12/1/2005
522
3/1/2013
120
3/1/2014
800
Question addressed
Status
Evaluate how well cholecalciferol supplementation works in regard to PSA response in localized PCa Evaluate the effect of risedronate vs placebo on bone mineral density in men undergoing ADT Study the time to treatment failure for ADT + zoledronic acid vs ADT alone in bone-metastasized PCa Can metformin can delay the time to progression in men with low-risk PCa vs placebo Compare standard of care in treating patients undergoing RT vs preventive treatment with Rapaflo Determine if early treatment with zoledronic acid is more efficacious than delayed treatment
Recruiting
Compare adverse effects of RT with docetaxel and short-course ADT vs RT with long-course ADT Determine if addition of radium-223 dichloride to standard treatment can prolong life and delay events specific for bone-metastasized PCa
Recruiting
Completed
Active, not recruiting
Recruiting
Not yet recruiting
Completed
Recruiting
PCa = prostate cancer; RT = radiotherapy; OS = overall survival; EBRT = external beam RT; LDR = low dose rate; RP = radical prostatectomy; ADT = androgen deprivation therapy; PSA = prostate-specific antigen; GnRH = gonadotropin-releasing hormone; BPFS = biochemical progression-free survival; NA = neoadjuvant; CRPC = castration-resistant prostate cancer; MCRPC = metastatic CRPC; DCVAC = dendritic cell vaccination; GTN = glyceryl trinitrate; GM-CSF = granulocyte-macrophage colony-stimulating factor.
Of the 71 trials testing systemic treatments alone, 34 (48%) tested androgen deprivation therapy (ADT). ADT duration was the question most commonly addressed, followed closely by optimal timing of ADT administration. This was followed by trials testing different types of chemotherapy (n = 15; 21%), immunotherapy (n = 9; 13%), and radiopharmaceutical (n = 2, 3%). Nine trials (13%) tested other systemic drugs and two (3%) tested a combination of systemic treatments (Table 2). In total, 23 trials were conducted on castration-resistant prostate cancer. Among the 34 trials investigating local treatments, radiation therapy was tested in 27 (79%), surgery alone in five (15%), and both radiation therapy and surgery in two (6%) trials (Table 3). The majority of trials on local treatments were conducted in intermediate-risk disease (n = 20; 59%), followed by low-risk (n = 15; 44%) and highrisk (n = 15; 44%) disease (data not shown). 4.
Discussion
Our results confirm that there is intense clinical trial activity on prostate cancer, with 123 phase 3 trials with pending results registered in the ClinicalTrials.gov database. Most trials identified were performed in North America or Europe and were designed to improve treatments for nonmetastatic prostate cancer (67%). More than half of all trials identified tested the effects of systemic treatment, some in patients with nonmetastatic disease. Given the awareness of the potential risks of overtreatment for
indolent prostate cancers [4,5], cure is not always achieved in patients with either aggressive localized, locally advanced, or locally recurrent disease [6]. This might be because at least some patients with nonmetastatic disease harbor micrometastatic disease. By contrast, patients with metastatic castration-resistant disease require more aggressive systemic therapy. Thus, improvements in systemic treatments even in the nonmetastatic setting are very important and might positively impact cancer control rates. Beside this clinical rationale, our finding that trials testing systemic treatments tended to be supported by industry may be another reason for the high rate of trials focusing on systemic treatments (even in nonmetastatic patients), reflecting certain company interests. Given the heterogeneity of patients with nonmetastatic prostate cancer, there is a need for improved patient stratification using novel biomarkers for prognostic and predictive guidance in deciding which patients would benefit most from which treatment approach, similar to the situation for breast and lung cancer. Unfortunately, it seems that phase 3 trials currently registered in the ClinicalTrials.gov database are not designed to improve this problem in the future, and are still only based on the TNM classification and Gleason grading systems. Trials focusing on local treatment methods much more commonly involved radiation therapy than surgery. This can be explained in part by technological innovations during the last two decades and the desire to validate
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
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EUROPEAN UROLOGY FOCUS XXX (2015) XXX–XXX
Table 3 – Trials investigating local treatments (n = 34; total accrual expected 27 306) ClinicalTrials.gov
Short name
Surgery (n = 5; 2392 patients) Obese patient during RARP: NCT01868347 preemptive ventilator strategy NCT01825642 NCT01613651 NCT01555086 NCT01407263
Seminal vesicle–sparing and nervesparing RP RALP with or without pelvic drain placement Extended vs limited pelvic lymphadenectomy during RP Trial of modifications to RP
Multiple interventions (n = 2; 8800 patients) PREFERE trial NCT01717677 Surgery vs RT for locally advanced PCa Radiation therapy (n = 27; 16 114 patients) 3D-conformal RT vs tomotherapy NCT00326638 NCT02102477
Start date (D/M/Y)
Planned accrual
2/1/2013
40
9/6/2014
140
8/12/2014
312
1/8/2011
500
7/1/2011
1400
1/10/2012
7600
1/10/2014
1200
11/5/2014
72
Question addressed
Preemptive PEEP vs PEEP after pneumoperitoneum and Trendelenburg Seminal vesicle–sparing vs nervesparing RP RALP with pelvic drain vs without Extended vs limited pelvic lymphadenectomy Fascial suturing RP vs lymph node template RP
3/1/2013
75
NCT01411345
MRI-mapped dose-escalated salvage RT
6/1/2011
80
NCT01230866
Hypofractionated proton RT For low-risk PCa HDR vs LDR brachytherapy
11/10/2014
192
10/1/2013
200
NCT00084552
IMRT with decreased radiation dose to erectile tissue vs without
12/1/2003
200
NCT01538628
SpaceOAR system pivotal study
1/1/2012
222
NCT00667888
IMRT dose escalation using hypofractionation Hypofractionated, dose escalation RT ADT with elective nodal and doseescalated RT Proton therapy vs IMRT
1/1/2001
225
1/1/2012
250
5/1/2004
400
7/1/2012
400
6/1/2003
588
10/1/2005
600
1/1/1998
602
4/6/2014
1115
5/1/2006
1204
3/1/2002
1532
7/1/2011
2580
1/1/2011
350
6/1/2013
350
10/1/2008
500
Finding the optimal dose
NCT01617161
NCT00063882 NCT00247312
Brachytherapy with or without EBRT 103 Pd dose de-Escalation brachytherapy
NCT00494039
125
NCT00331773
RT in treating patients with stage II PCa Profit: prostate fractionated irradiation trial RT In treating patients with stage II PCa ADT and RT in treating patients with PCa
NCT00304759 NCT00033631 NCT01368588
NCT01272050 NCT01839994
NCT00967863
I vs
103
Pd brachytherapy
RT in treating patients with relapsed PCa after surgery Conformal RT alone vs conformal RT combined with HDR brachytherapy or SBRT for PCa RT in treating patients receiving ADT for PCa
Recruiting Recruiting Recruiting
Recruiting
Hypofractionation via extended vs accelerated RT
NCT00175396
Completed
Recruiting
NCT01794403
NCT01444820
Recruiting
Active surveillance vs RP vs EBRT vs brachytherapy RP vs RT
Side effect reduction through IMRT compared to 3D-conformal RT Accelerated hypofractionated regimen will not be inferior to the standard treatment An increased dose to the MRI-defined lesion in the prostate bed will result in better initial CR Compare hypofractionation to standard proton RT HDR boost will achieve better PFS compared to LDR with a better toxicity profile and QoL Erectile dysfunction rate reduction when restricting the dose to erectile tissue Safety and reduction of toxicity using the SpaceOAR system Is hypofractionated IMRT as good or better than conventional RT Safety evaluation of dose-escalated hypofractionated RT Is a brachytherapy boost better than an EBRT boost Evaluation of whether fewer side effects occur for proton therapy compared to EBRT Brachytherapy better with or without EBRT for intermediate-risk PCa A 10% reduction in applied dose could reduce side effects while still being adequate The shorter half-life of 103Pd vs 125I will increase the rate of tumor eradication Comparison of different RT regimens, hypofractionation results Evaluation of hypofractionation results Compares the effectiveness of two different IMRT doses Better overall survival OS When the RT Volume Is Increased On The Whole Pelvis Comparison of two salvage doses for biochemically recurrent PCa Outcome comparison
NCT01936883
Status
Not yet recruiting
Recruiting
Recruiting
Recruiting Not yet recruiting
Active, not recruiting
Active, not recruiting Active, not recruiting Recruiting Active, not recruiting Recruiting
Active, not recruiting Recruiting
Active, not recruiting
Active, not recruiting Active, not recruiting Active, not recruiting Recruiting
Active, not recruiting Not yet recruiting
Recruiting
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
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Table 3 (Continued ) ClinicalTrials.gov
Short name
Start date (D/M/Y)
Planned accrual
FLAME: investigate the benefit of a focal lesion ablative microboost in PCa Triptorelin and RT after surgery for intermediate-risk stage III or IV PCa
9/9/2014
566
12/1/2007
718
10/1/2002
2163
NCT00860652
IMRT in treating patients with localized PCa Trial to evaluate RT followed by ADT vs ADT alone for PSA failure after RP Adjuvant vs early salvage RT
NCT01550237
Curative image-guided RT for PCa
NCT01168479
NCT00667069
NCT00392535 NCT00138008
5/1/2004
200
3/1/2009
470
1/10/2012
260
Question addressed SIB to the focal lesion could produce better results without increased toxicity Compare the results of ADT + RT immediately after surgery vs delaying treatment Comparison of the side effects of three IMRT schedules Comparison of RT with ADT to ADT alone after biochemical recurrence Comparing adjuvant vs early salvage RT in PCa with positive margins or extraprostatic disease following RP Investigate whether cone beam IGRT and consequently reduced safety margins can reduce rectal side effects
Status Recruiting
Recruiting
Recruiting Recruiting
Recruiting
Recruiting
PCa = prostate cancer; RP = radical prostatectomy; RARP = robot-assisted RP; PEEP = positive end expiratory pressure; RT = radiotherapy; SBRT = stereotactic body RT, IMRT = intensity-modulated RT; IGRT = image-guided RT; EBRT = external beam RT; HDR = high dose rate; LDR = low dose rate; SIB = simultaneous integrated boost; ADT = androgen deprivation therapy; PSA = prostate-specific antigen; MRI = magnetic resonance imaging; NA = neoadjuvant; CR = complete response; QoL = quality of life.
Table 4 – Trials investigating both local and systemic treatments (n = 11, total expected accrual 19 822) ClinicalTrials.gov
Short name
Start date (D/M/Y)
Planned accrual
NCT01546623
Comparative study of TAP-144-SR in PCa patients previously treated with ADT
3/1/2012
164
NCT02044172
ProtecT trial: prostate testing for cancer and treatment Single-dose local RT compared with ibandronate in treating patients with localized metastatic bone pain
6/1/2001
1500
4/3/2014
580
Cabazitaxel and pelvic RT in localized PCa and high-risk features of relapse STAMPEDE trial: systemic therapy in advancing or metastatic PCa: evaluation of drug efficacy RT with or without bicalutamide and goserelin in treating patients with PCa Study on the role of hormonal treatment for two dosage levels of prostate RT vs prostate RT alone A phase 3 trial of ADT local RT abiraterone in metastatic hormonenaı¨ve PCa Prostate RT or short-term ADT and pelvic lymph node RT with or without prostate RT in treating patients with rising PSA after surgery for PCa RADICALS: RT And ADT in treating patients who have undergone surgery for PCa Surgery with or without docetaxel and leuprolide or goserelin for highrisk localized PCa
9/13/2014
1048
9/5/2014
8100
5/1/2003
400
12/1/2000
600
10/1/2013
916
NCT00082927
NCT01952223
NCT00268476
NCT00067015
NCT00223145
NCT01957436
NCT00567580
NCT00541047
NCT00430183
2/1/2008
1764
10/1/2007
4000
12/1/2006
750
Question addressed
Hormone dynamics, pharmacokinetics, safety and efficacy of TAP-144-SR for 6 mo vs 3 mo Active surveillance vs RP vs RT plus ADT Comparing pain response of ibandronate vs single-dose local RT with 8 Gy in treating patients with localized metastatic bone pain Assess the effect on clinical PFS of NA cabazitaxel and pelvic RT with ADT vs prostate-only RT with ADT Assessment of 5 treatments usually held for CRPC used sooner in combination with ADT Comparing QoL of high-dose IMRT to 86.4 Gy alone vs IMRT To 75.6 Gy plus NA/adjuvant ADT Would adding 6 mo of ADT lead to local failure reduction when using 70 or 76 Gy vs 76 Gy alone Compare the clinical benefit of ADT local RT abiraterone acetate and prednisone in metastatic PCa Comparing prostate RT to shortterm ADT with pelvic lymph node RT prostate RT in biochemically recurrent PCa RT timing (adjuvant vs early salvage) and ADT duration after local surgery Comparing NA docetaxel and ADT vs surgery alone in patients with high-risk localized PCa
Status
Recruiting
Active, not recruiting Completed
Recruiting
Recruiting
Completed
Active, not recruiting
Not yet recruiting
Recruiting
Recruiting
Recruiting
PCa = prostate cancer; RT = radiotherapy; IMRT = intensity-modulated radiotherapy; RP = radical prostatectomy; CRPC = castration-resistant PCa; ADT = androgen deprivation therapy; PSA = prostate-specific antigen; PFS = progression-free survival; NA = neoadjuvant; QoL = quality of life.
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
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11
Fig. 3 – Circle diagram characterizing the trials identified.
these advances in clinical trials. Surprisingly, the heavily debated topic of focal therapy is being analyzed in just two phase 3 randomized clinical trials that we identified, NCT01168479 (one of the seven uncategorized trials) and NCT01310894. An additional search in the original database of 2951 prostate trials identified revealed more than 30 phase 1 and phase 2 trials on focal therapy that are ongoing or completed. This supports the previously expressed concern that focal therapy remains in its infancy and should thus only be regarded as an experimental approach [7]. Technological advances in robotics and its application in localized disease have not yet been verified in phase 3 randomized clinical trials. Only two trials directly compared surgery to radiation therapy, the ProtecT trial (NCT02044172) and the PREFERE trial (NCT01717677).
Our analysis is not without limitations. Not every clinical trial is registered on ClinicalTrials.gov; registration is obligatory for all US studies, but not for non-US trials. Therefore, possible selection bias regarding our findings for trial locations is possible. Nevertheless, as ClinicalTrials.gov is the largest global trials registry database available, with 52% of all registered trials non–US-based, our findings provide a representative, if not complete, picture of current research in prostate cancer. Some trials might have been incorrectly registered in the ClinicalTrials.gov registry. Moreover, we cannot exclude the possibility of errors whereby certain trials were not captured for the analysis and/or were misclassified during the selection process. In addition, the data sets for all trials in the database are not always complete and up to date. However, we took great care to minimize these limitations: two authors
Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003
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(A.T. and P.G.) crosschecked all trials identified and the trial selection steps. We believe that our analysis is unique and important, and that the comprehensive tables provide researchers and clinicians with a realistic picture of the future of prostate cancer treatment. 5.
Conclusions
Our analysis demonstrates strong ongoing clinical research activity that will undoubtedly impact on the future of prostate cancer treatment worldwide. Most of the phase 3 trials with pending results address questions regarding systemic treatments for both nonmetastatic and metastatic disease. In the subgroup of trials testing local treatments, radiation therapy is the focus of the majority of investigations and shows the greatest potential for further improvement.
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: None. Funding/Support and role of the sponsor: None.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. euf.2015.05.003.
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Financial disclosures: Pirus Ghadjar certifies that all conflicts of interest,
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including specific financial interests and relationships and affiliations
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Please cite this article in press as: Tsikkinis A, et al. Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. Eur Urol Focus (2015), http://dx.doi.org/10.1016/j.euf.2015.05.003