Pre-clinical research and early phase clinical trials provide vital evidence for novel drug development, safety and efficacy. Only a small number of cancer drugs that demonstrated promising results pre-clinically are shown to be safe and effective in humans. Unsuccessful phase 3 trials may be due to poor or lack of pre-clinical and clinical evidence, leading to disappointing results for patients, clinicians and investigators. The aim of this review was to assess castrate resistant prostate carcinoma phase 3 trial protocols for documentation of pre-clinical and clinical evidence, assessing both successful and unsuccessful drugs.
Protocols were requested for pivotal castrate resistant prostate carcinoma phase 3 clinical trials. Sources included journal publications, principal investigators, industry sponsors and Project Data Sphere (online trial sharing programme). Both successful and unsuccessful drugs were assessed. Published pre-clinical evidence that protocols were assessed for included relevant disease and treatment pathophysiology, drug development (biochemistry, pharmacology), in vitro experiments (cell lines) and in vivo experiments (animal, prostate carcinoma specific mice xenograft and patient derived xenograft). Published clinical evidence assessed for included phase 1, 2 and 3 trials.
Protocols were obtained for 24 of 36 nominated pivotal trials. 10 (42%) were for successful drugs (docetaxel, cabazitaxel, abiraterone, enzalutamide, sipuleucel-T, radium-223 and apalutamide) and 14 (58%) were for unsuccessful drugs (cabozantinib, ipilimumab, bevacizumab, orteronel, sunitinib, tasquinimod, atrasentan, zibotentan, aflibercept, lenalidomide, custirsen and calcitriol). Pre-clinical evidence was reported as follows: disease or treatment pathophysiology in 18 trials (75%), drug development 12 (50%), animal studies 4 (16.6%), cancer cell line 7 (29%), mice xenograft 8 (33.3%) and patient derived xenograft 3 (12.5%). Clinical evidence was reported as follows: phase 1 trial in 15 trials (62.5%), phase 2 trial 12 (50%) and phase 3 trial 2 (8.3%). Successful phase 3 trials were associated with higher numbers of previous phase 1 and 2 trials.
Documentation of pre-clinical and clinical evidence was poor in castrate resistant prostate carcinoma phase 3 trial protocols. Two thirds reported a preceding phase 1 trial, but only 50% reported a phase 2 trial. Frequently, unpublished or preliminary results and evidence from other malignancies were included in protocols. This evidence was not included in this review. Basic and translational research has significantly increased over the years, explaining why older studies tended to report less pre-clinical evidence. It is possible that sound pre-clinical evidence existed and was not reported in protocols, sometimes reported when results were later published in journals. Rushing drugs to phase 3 trials can be rewarding if successful, but if inappropriate can have devastating consequences of toxicity or inefficacy. 12 trial protocols were unobtainable due to lack of publication and older trials not having electronic copies. We aim to obtain more protocols for assessment.