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To improve treatments for patients with castration-resistant prostate cancer, new biomarkers and surrogate end points for clinical trials are required. Identifying biomarkers that reflect clinical benefit and that guide personalized treatment plans are of the highest priority. This Review article outlines the framework for developing such biomarkers, including analytical validation, clinical validation and regulatory approval, and describes promising emerging biomarkers.

Options to treat late-stage castration-resistant prostate cancer continued to increase in 2011, as three agents with different mechanisms of action prolonged life and a fourth reduced the morbidity of skeletal metastases. These outcomes contrasted with the heightened controversy generated by the recommendation against PSA screening and other early detection strategies.

Post-therapy prostate-specific antigen (PSA) changes have been associated with improved survival in castrate metastatic patients, but currently no drug has been approved strictly on the basis of a post-treatment decline in PSA, as it is unproven that such PSA changes are surrogates for true clinical benefits. Fleming and coauthors address the critical question of whether PSA post-therapy decline reflects true clinical benefit, and if it should be used as an intermediate endpoint for accelerated approval. The authors emphasize the importance of recognizing that there are a range of clinical benefits to patients that can favorably improve the quality and possibly the duration of survival independent of PSA.

In two recent phase III trials, investigators evaluated the addition of docetaxel to androgen-deprivation therapy for non-castrate prostate cancer. On the basis of the CHAARTED-trial findings, we can firmly conclude that this combination can be used in the metastatic setting. The results of the GETUG 12 trial are less informative, although some benefit for patients with high-risk localized prostate cancer was demonstrated.

High-risk prostate cancer includes a heterogeneous group of patients with a range of prognoses, with some that can be fatal. The optimal management of this patient subgroup is evolving. We critically evaluate the existing literature focused on defining the high-risk population, the management of patients with high-risk prostate cancer, and future directions to optimize care.

Clinical trials are an essential aspect of drug development; however, in patients with non-castrate prostate cancer, the long natural history of the disease provides a major barrier to the introduction of new therapies. In this Review, the authors describe the potential of a novel, multi-arm, multistage, clinical trial project, with surrogate end points designed to fully reflect the effects of treatments, in transforming the treatment of patients with early stage prostate cancer, before the development of castration-resistant disease.

Here, the authors discuss issues relating to the co-development of targeted cancer therapies and companion diagnostics that were not covered in depth in the draft guidance released by the US Food and Drug Administration in 2011. They propose potential strategies that will be useful to mitigate challenges and to help guide the future co-development of drugs and diagnostics.