Randomised phase III trials of cancer prevention drugs: a systematic review and prediction of trial success

Abstract

BACKGROUND: Pharmacological cancer risk reduction has received far less investment than therapeutic oncology and only a few agents have entered routine practice. Understanding the predictors of positive outcomes of previous trials and issues faced is critical to future developments. METHODS: This systematic review (PROSPERO CRD420250650276) included all phase III randomised controlled trials enrolling cancer-free adults over the past 45 years, evaluating pharmacological agents and whose primary or major secondary endpoint was directly related to cancer risk reduction. To predict trials' 'success', defined here as meeting the prespecified cancer risk reduction-related endpoint within the planned timeline, we used the Least Absolute Shrinkage and Selection Operator followed by multivariable logistic regression. RESULTS: Ninety-two trials comprising 659 904 participants were included, of which 46 (50.0%) met their primary endpoint. Success rates varied by therapeutic class: vitamins (9 of 38, 23.7%), endocrine therapies (15 of 20, 75.0%), nonsteroidal anti-inflammatory drugs (8 of 13, 61.5%), human papillomavirus vaccines (8 of 9, 88.9%) and anti-infective agents (5 of 8, 62.5%). Proportionally, breast (76.5%), cervical (72.7%) and oesophagogastric (58.3%) cancer risk reduction trials had the highest success rates versus 23.7% for vitamins trials. Adherence was highest for vaccines [median 95%, interquartile range (IQR) 93%-96%] and lowest for endocrine therapies (median 70%, IQR 65%-78%). Major safety issues arising for a dozen of the drugs limited their approval (n = 5) and use. In the multivariable analysis, the odds of success increased for trials with pharmaceutical sponsorship [odds ratio (OR) 5.30, 95% confidence interval (CI) 1.01-35.77] and decreased for non mechanism-specific drugs and for studies with lower pretrial evidence (OR 0.30, 95% CI 0.10-0.90). CONCLUSIONS: Although half of the pharmacological cancer risk reduction trials conducted so far have shown positive results, only a handful have led to regulatory approval. Trial success was driven by more targeted strategies and strong preliminary evidence, underscoring the need for mechanism-driven, strong-evidence development pathways in cancer risk reduction.