With the approval of several novel agents in the last 4 years, patients are likely to be exposed to several survival-prolonging treatments, impacting OS benefits from an experimental therapy tested as an early line of treatment. A median OS benefit for a novel agent may therefore no longer be an achievable endpoint. With the COU-AA-302 trial pre-chemotherapy abiraterone was only licensed based on the proven survival benefit post-docetaxel and the significant improvement in the co-primary and all secondary endpoints. However, orteronel (TAK-700) may be the first casualty of the increased access to active post-trial therapies. The changing landscape of drug development in CRPC therefore urgently requires validation of intermediate endpoints.

In order to fulfill the criteria of surrogacy a biomarker must meet several prospectively defined criteria (termed the Prentice Criteria) and must be validated across multiple trials of different anticancer treatments [41]. At present there are no surrogate endpoints for OS in CRPC. Decreases in circulating tumor cell (CTC) counts and the combination of CTCs and LDH have shown promise as survival surrogates [42, 43].

At least 20 baseline (pre-treatment) and eight on-treatment factors have been shown to have prognostic significance in CRPC patients [44]. These factors were combined into nomograms that predicted survival for chemotherapy-naïve CRPC patients [45–48]. These nomograms were developed before the introduction of the novel treatments and require updating for contemporary CRPC populations [49].

Increasing use of molecular characterization technologies may soon allow CRPC patients to be stratified within trials, or for development of niche therapies targeting key mutations in subsets of CRPC patients. Although these approaches are likely to improve response rates, challenges of molecular heterogeneity within tumors and patients, as well as parallel signaling pathways within cancer cells, will need to be addressed moving forward.

Translational studies often require tissue and mandating available blocks or slides at study entry is one method for protecting the validity of these important exploratory objectives. Although prostate cancer most commonly metastasizes to bone, making biopsy more challenging, the ability to maximize opportunities for prostate cancer patients to participate in both cancer-specific and solid tumor Phase I studies should encourage clinicians to pursue tissue acquisition whenever possible.