Charles Sawyers (Memorial Sloan-Kettering Cancer Center, New York, NY, USA), opened the AACR-NCI-EORTC session on drug resistance in targeted agents with a keynote lecture on prostate cancer acquired drug resistance to antiandrogen agents, as a paradigmatic case study of targeted resistance drugs in cancer.

The unresolved issues with prostate cancer are still manifold. First, prostate cancer is a highly heterogeneous disease, and currently there is still no clinically relevant scheme for sub-classifying patients in terms of treatment and prognosis. Secondly and correlated to this first point, there is an urgent need of a good biomarker which can predict the prognosis and guide the stratification of patients and therapies. Indeed, the current biomarker used for prostate cancer, PSA, does not meet these requirements, as it does not predict survival benefit. Finally, prostate cancer is a difficult disease to tackle, due to the widespread phenomenon of acquired resistance, which was the main focus of Charles Sawyers' lecture. The data are telling: while most patient (75-80%) respond dramatically to antiandrogens (eg bicatulamide, flutamide), most will develop resistance in a couple of years.

A second generation of antiandrogens able to overcome this resistance is therefore desperately needed. One strategy, adopted by Samedy Ouk and Michael Junh, UCLA, and supported by Sawyers, is to look for antiandrogens which display stronger antagonist than agonist features. Such agents would be able to overcome the antagonist/agonist conversion which is thought to be responsible for the actual mechanism of resistance of traditional antiandrogen agents such as bicatulamide and flutamide.

One promising candidate currently under screening is a drug named MDV3100, which binds androgen receptors with > 5 fold greater affinity than bicalutamide (Tran et al, Science 2009). Currently, a phase 1-2 multicenter first in man trial of MDV3100 in castrate resistant prostate cancer is ongoing.

From a broader perspective, Sawyers stressed the need to 'be smarter' in early clinical trial development. In other words, according to Sawyers there are a few 'rules' which, even if not easy to follow, would assure a successful translation from the bench to bedside. Namely, these 'rules' would require investigators to:

a) test drugs in patients whose tumours are dependent on the target;

b) conduct the trial in a manner such that the researcher can know if and when the drug hits the target;

c) develop a readout of clinical activity which can be obtained in weeks (rather than months or years), for instance a good blood based serum marker, or a FDG-PET scan.

The most important take-home messages from Sawyers' lecture seem therefore to be the following: 1) the stratification of the patients in respondents versus non respondents should be done, whenever possible, before the initiation of any clinical trial; and 2) the result of the trial should be a go/no go decision concerning the future development of the agent.

These are also the assumptions underlying the recent FDA guidance on early exploratory investigational new drug studies, also known as Phase 0 trials, which were mentioned by Sawyers as a promising strategy to fill the current gap in translational research.

References

Druker BJ, Talpaz M, Resta DJ, et al.Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001:344(14):1031-7.

Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009;324(5928):787-90.

FDA 2006 Guidance for Industry, Investigators, and Reviewers on Exploratory IND Studies, available at  http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078933.pdf (retrieved November 16, 2009).