ISTs tend to focus on novel drug development, while IITs may investigate alternative indications to standard of care drugs, biomarker selection, treatment de-intensification, and real-world outcomes. Despite significant progress in the management of genitourinary (GU) cancers in recent years through clinical trials, little is known about the trends and characteristics of ISTs and IITs driving these changes in practice.
To investigate this, we analyzed 5,834 GU cancer clinical trials in prostate, bladder, and kidney cancer, registered with ClinicalTrials.gov from January 2007 to December 2021. These trials were conducted in the United States (US) (n=3814), Canada (n=709), France (n=677), and the United Kingdom (UK) (n=634). We characterized these trials based on funding sources, participant numbers, trial types, and several key elements of trial design, to better understand trends over the last 15 years.
The results showed that the majority of ISTs were phase 3 trials with over 500 participants, whereas IITs were primarily open-label phase 2 studies with only 20-49 participants (Table 1).
Table 1: Characteristics of IIT categorized by country
|
US (n=1974) |
Canada (n=321) |
France (n=285) |
UK (n=190) |
||
|
Type |
Interventional Observational Missing |
1622 (82%) 352 (18 %) 0 |
274 (85%) 47 (14.8%) 0 |
201 (71%) 82 (29%) 2 (0.7%) |
128 (67%) 62 (33 %) 0 |
|
Purpose |
Treatment Translational Diagnostic Health services Prevention & Screening Supportive Care Other Missing |
1040 (52.7) 22 (1.1) 222 (11.2%) 42 (2.1%) 93 (4.7%) 171 (8.7%) 39 (2.0%) 345 (17.5%) |
166 (51.7) 5 (1.6%) 36 (11.2%) 4 (1.3%) 18 (5.6%) 33 (10.3%) 12 (3.7%) 47 (14.6%) |
99 (34.7%) 10 (3.5%) 40 (14.0%) 2 (0.7%) 11 (3.8%) 8 (2.8%) 25 (8.8%) 90 (31.6%) |
73 (38.4%) 6 (3.2%) 15 (7.9%) 4 (2.1%) 7 (3.7%) 7 (3.7%) 12 (6.3%) 66 (34.7%) |
|
Phase |
Early phase 1 Phase 1 Phase 1/2 Phase 2 Phase 2/3 Phase 3 Phase 4 Other Missing |
80 (4.0%) 244 (12.4%) 105 (5.3%) 552 (28.0%) 22 (1.1%) 88 (4.5%) 16 (0.8%) 539 (27.3%) 328 (16.6%) |
1 (0.3%) 17 (5.3%) 14 (4.3%) 66 (20.6%) 10 (3.1%) 36 (11.2%) 6 (1.9%) 126 (39.3%) 45 (14.0%) |
2 (0.7%) 5 (1.8%) 6 (2.1%) 51 (17.9%) 3 (1.0%) 18 (6.3%) 3 (1.0%) 113 (39.7%) 84 (29.4%) |
2 (1.1%) 3 (1.6%) 7 (3.7%) 31 (16.3%) 4 (2.1%) 17 (9.0%) 2 (1.1%) 62 (32.6%) 62 (32.6%) |
|
Number of participants |
0 to 49 50 to 99 100 499 500+ Missing |
1096 (55.5%) 291 (14.7%) 415 (21.0%) 172 (8.7%) 0 |
144(44.9%) 55 (17.1%) 82 (25.5%) 40 (12.5%) 0 |
96 (33.7%) 60 (21.0%) 94 (33.0%) 33 (11.6%) 2 (0.7%) |
59 (31.1%) 40 (21.1%) 53 (27.9%) 37 (19.5%) 1 (1.0%) |
|
Masking |
Open label Single-blinded Double-blinded Triple blinded Quadruple blinded Other Missing |
1413 (71.6%) 79 (4.0%) 76 (3.8%) 37 (1.9%) 19 (1.0%) 348 (17.6%) 2 (0.1%) |
227 (70.7%) 20 (6.2%) 9 (2.8%) 8 (2.5%) 10 (3.1%) 47 (14.6%) 0 (0%) |
187 (65.6%) 5 (1.8%) 1 (0.4%) 3 (1.0%) 4 (1.4%) 82 (28.8%) 3 (1%) |
101 (53.2%) 5 (2.6%) 6 (3.2%) 2 (1.1%) 6 (3.2%) 62 (32.6%) 8 (4.0%) |
|
Assignment |
Single group Parallel Crossover Factorial Other Missing |
914 (46.3%) 641 (32.5%) 21 (1.0%) 10 (0.5%) 352 (17.9) 36 (1.8%) |
131 (40.8%) 130 (40.5%) 6 (1.9%) 5 (1.6%) 47 (14.6%) 2 (0.6%) |
106 (37.2%) 84 (29.5%) 3 (1.0%) 1 (0.4%) 82 (28.8%) 9 (3.1%) |
45 (23.7%) 58 (30.5%) 0 5 (2.6%) 62 (32.6%) 20 (10.5%) |
|
Treatment Allocation |
Randomized Non-randomized Other Missing |
566 (28.7%) 235 (11.9%) 352 (17.8%) 821 (41.6%) |
133 (41.4%) 29 (9.0%) 47 (14.6%) 112 (34.9%) |
65 (22.8%) 36 (12.6%) 82 (28.8%) 102 (35.8%) |
74 (39.0%) 6 (3.2%) 62 (32.6%) 48 (25.3%) |
In the US, the ratio of ISTs and IITs was relatively balanced; however, Canada, France, and the UK demonstrated an increasing predominance of ISTs, particularly after 2017 (Table 2).
Table 2: IST and IIT in GU oncology conducted from 2007-2021
|
|
US, n=3814 (%) |
Canada, n=709 |
France, n=677 |
UK, n=634 |
||||
|
|
IST |
IIT |
IST |
IIT |
IST |
IIT |
IST |
IIT |
|
2007 to 2011 |
453 (45.3)
|
547 (54.7)
|
110 (55.0) |
90 (45.0) |
96 (61.1) |
61 (38.9) |
105 (66.9) |
52 (33.1) |
|
2012 to 2016 |
529 (45.1) |
643 (54.9) |
118 (48.2) |
127 (51.8) |
116 (57.7) |
85 (42.3) |
140 (67.6) |
67 (32.4) |
|
2017 to 2021 |
858 (52.3) |
784 (47.7) |
160 60.6 |
104 39.4 |
180 (56.4) |
139 (43.6) |
199 (73.7) |
71 (26.3) |
In all four countries, a greater proportion of results were reported from ISTs than IITs, especially in France and the UK. (Figure 1).
Figure 1: Proportion of trials with results posted per year for A) US, B) Canada, C) France, D) UK
This study underscores a widening gap between ISTs and IITs in GU oncology, likely influenced by funding constraints for IITs. In the US, research grant support from government agencies, and major oncologic societies such as the American Society of Clinical Oncology (ASCO), Prostate Cancer Foundation (PCF), and Bladder Cancer Advocacy Network (BCAN) continue to facilitate the development of IITs.2,3,4 Similar funding approaches could be explored in Canada, France, and the UK. Moreover, dedicated support and resources for study design, protocol development, statistical analysis, budget, contract negotiations, and regulatory submissions, may further help mitigate barriers for IIT development. Collaborative efforts among investigators and cooperative groups have been successful for this process, and have led to pivotal practice-changing IITs, such as the CHAARTED, ENZAMET, and STAMPEDE trials through the ECOG-ACRIN Cancer Research Group, Australian and New Zealand Urogenital and Prostate (ANZUP) and Cancer Research UK respectively.5,6,7 Several practice changing IITs have also been led by multi-cooperative groups collaboration (Intergroup trials), such as the NCIC CTG PR.3/Medical Research Council (MRC) UK PR07, which can help overcome regulatory barriers for multicentered international studies.8
Limitations of our study include a focus on only 4 countries and a primary emphasis on quantifying key characteristics and overall trends in GU trials. As such we did not conduct a detailed comprehensive analysis of IST and IIT with respect to funding, time to trial completion and publication, and other variables, or examine qualitative barriers for IIT development. Nonetheless, our findings highlight the significant gaps in IITs and the potential negative impact on the development of patient-centric management strategies. Further research is warranted to inform strategies to enhance IIT development in GU oncology.
Written by: Jenny Peng, MD FRCPC, Di Maria Jiang MD, MSc, FRCPC, and Srikala S. Sridhar MD, MSc, FRCPC
Princess Margaret Cancer Center, Toronto, Ontario, Canada
References:
- Blümle A, Wollmann K, Bischoff K, Kapp P, Lohner S, Nury E, et al. Investigator initiated trials versus industry sponsored trials - translation of randomized controlled trials into clinical practice (IMPACT). BMC Med Res Methodol. 2021 Dec 31;21(1):182.
- ASCO continues to advocate for congress to prioritize cancer research funding in 2024. Alexandria, VA: ASCO in Action, 2023.
- Millions in new federal funding for prostate cancer research. Santa Monica, CA: Prostate Cancer Foundation, 2022.
- Our legislative priorities. Bethesda, MD: Bladder cancer advocacy network. Accessed Mar 5, 2024.
- Kyriakopoulos C, Chen YH, Carducci M, Liu G, Jarrard D, Hahn N, Shevrin D et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: Long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018 Apr 10; 36(11): 1080-1087.
- UroToday. Impact of academic collaborations in mHSPC trial: ENZAMET - Chris Sweeney. 2019 [cited 2023 Jan 26]; Accessed Jan 24, 2023.
- Carthon, BC ∙ Antonarakis, ES. The STAMPEDE trial: paradigm-changing data through innovative trial design. Transl Cancer Res. 2016; 5:S485-S490.
- Mason M, Parulekar WR, Sydes M, Brundage M, Kirkbride P, Gospodarowicz M et al. Final Report of the Intergroup Randomized Study of Combined Androgen-Deprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally Advanced Prostate Cancer. 2015 Jul 1; 33(19): 2143-50.