Clinical trial risk in castration-resistant prostate cancer: immunotherapies show promise.

OBJECTIVES: To determine the risk of failure during drug development in castration-resistant prostate cancer (CRPC) and to identify factors that could improve outcomes. METHODS: We investigated CRPC by analysing compounds in phase I to phase III clinical trials between 1998 and April 2011. Drug development failures were classified as medical or commercial and were compared with industry expectations. Compounds were excluded from analysis if their phase I occurred before 1998, if they targeted patients that were did not have hormone-refractory prostate cancer, or if they did not assess outcomes such as overall survival, time to disease progression, or prostate-specific antigen levels. RESULTS: Thorough searches of clinicaltrial.gov and other databases yielded 77 compounds that met the inclusion criteria. The cumulative pass rate for first-line compounds in CRPC was 3% and was far below aggregate industry expectations. In total, there were nearly equivalent numbers of commercial and medical failures. Biological products were found to have had greater relative success than small-molecule drugs and biotechnology firms had been slightly more successful than pharmaceutical firms in this disease indication. Phase III failures were high, despite equally high failures during phase II. CONCLUSIONS: Currently, one in 33 compounds that enters clinical testing will be awarded US Food and Drug Administration approval. This appears to be the highest risk indication investigated to date, based on clinical trial studies alone, with an average cost of $1.411bn to bring a new drug to market when adjusted for risk. Development of radical therapeutics such as immunotherapies may also be warranted instead of classic antineoplastic therapeutics. Given the high clinical trial risk, efforts may have to shift to biomarker and surrogate endpoints to manage future clinical trial risk in prostate cancer.