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BRCA Gene Mutations in Cancer · Review
ESMO Open · September 9, 2026
Well-designed and adequately powered for the question it asks.
This systematic review of 92 phase III cancer prevention trials involving 659,904 participants found that 46 (50.0%) met their primary endpoints, with success strongly associated with pharmaceutical sponsorship (OR 5.30, 95% CI 1.01–35.77) and mechanism-specific, evidence-driven strategies. Success rates varied markedly by therapeutic class: vaccines achieved 88.9% success, endocrine therapies 75.0%, and vitamins only 23.7%, suggesting that targeted, hypothesis-driven approaches outperform general pharmacological agents in cancer risk reduction trials.
Systematic review of phase III randomised controlled trials. Cancer-free adults enrolled in phase III randomised controlled trials evaluating pharmacological agents for cancer risk reduction.. Intervention: Pharmacological cancer risk reduction agents (vitamins, endocrine therapies, nonsteroidal anti-inflammatory drugs, human papillomavirus vaccines, anti-infective agents).. Compared with: Placebo or standard of care (implicit in phase III RCT design; specific comparators per trial not detailed).. n = 659,904. Not specified in source.
46 of 92 trials (50.0%) met their prespecified cancer risk reduction endpoints. Vaccine trials showed highest success rate at 8 of 9 (88.9%), followed by endocrine therapies at 15 of 20 (75.0%), compared to vitamins at 9 of 38 (23.7%). Pharmaceutical sponsorship increased odds of success (OR 5.30, 95% CI 1.01–35.77); lower pretrial evidence decreased odds (OR 0.30, 95% CI 0.10–0.90).
Pharmaceutical sponsorship increased odds of success (OR 5.30, 95% CI 1.01–35.77); lower pretrial evidence decreased odds (OR 0.30, 95% CI 0.10–0.90). Major safety issues limited approval or use of 12 drugs; only a handful of trials led to regulatory approval despite 50% positive outcome rate.
Clinicians and trial designers should prioritise mechanism-specific, hypothesis-driven cancer prevention strategies with strong preclinical evidence over broad-spectrum agents like vitamins. The low conversion from positive trial outcomes (50%) to regulatory approval highlights the importance of integrated safety monitoring and real-world adherence planning, particularly for long-term preventive therapies.
A rigorous systematic review of 92 phase III RCTs over 45 years with 659,904 participants, using prespecified definitions of success and multivariable logistic regression to identify predictors of trial outcomes in cancer prevention.
As stated by the source record.
Quoted from the source exactly as published.
Clinicians and trial designers should prioritise mechanism-specific, hypothesis-driven cancer prevention strategies with strong preclinical evidence over broad-spectrum agents like vitamins. The low conversion from positive trial outcomes (50%) to regulatory approval highlights the importance of integrated safety monitoring and real-world adherence planning, particularly for long-term preventive therapies.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
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.
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