Emerging Challenges of Prostate Cancer Drug Development

6/6/12Follow @3nt

The world’s largest cancer meeting of scientists, physicians and industry has just ended in Chicago. The annual meeting of the American Society of Clinical Oncology (ASCO) attracted over 30,000 attendees to hear leading experts on the latest in cancer drug development.

From what I heard at ASCO, biotechnology and pharmaceutical companies with new prostate cancer products in development or those seeking to enter this increasingly crowded market will face a number of challenges. A few of these are:

1. Overall survival (OS), i.e. whether will men live longer, is still the endpoint expected by regulatory agencies for marketing approval

With the exception of the COU-AA-302 trial for Johnson & Johnson’s abiraterone acetate (Zytiga) that was presented at ASCO this year, all the recent Phase III trials in metastatic castration-resistant prostate cancer—a form of disease that has spread and no longer responds to traditional chemical castration therapies—have shown a significant overall survival advantage. Consider the chart below:

Product Trial Name OS advantage (median # of months) FDA status
Docetaxel TAX 327 2.4 Approved
Sipuleucel-T Impact 4.1 Approved
Cabazitaxel Tropic 2.4 Approved
Abiraterone COU-AA-301 3.9 (updated to 4.6 at ASCO 2011) Approved
Radium-223 Alsympca 2.8 (updated to 3.6 at ASCO 2012) Application expected 2nd half 2012
Enzalutamide (formerly MDV3100) Affirm 4.8 Filed for approval May 22, 2012

In order to show a survival advantage, companies have been doing clinical trials with men at the most advanced stage of prostate cancer, in the post-chemotherapy setting.

In the future, it will be harder to show an advantage in overall survival as companies will have to do clinical trials to show their product is equal or superior to products such as J&J’s abiraterone, Medivation’s enzalutamide, and Algeta’s radium-223 (Alpharadin) that are changing the standard of care. I think we have reached or will soon reach the end of the use of placebo-controlled trials in advanced prostate cancer.

2. Progression Free Survival (PFS)—a measurement of whether a drug can delay the spread of tumors—does necessarily not mean a drug will help patients live longer.

At ASCO in an education session on castration-resistant prostate cancer, Dr. Andrew J. Armstrong, an associate professor of medicine at Duke University, illustrated examples of why certain surrogate markers in clinical trials—which researchers use to gauge whether a drug is working before long-term survival data is available—aren’t always reliable. In the case of prostate cancer, measurements of disease progression (PFS) did not correlate in the end with overall survival (OS) in many clinical trials, Armstrong said. Improvements in PFS DO NOT always lead to OS improvements, he said.

Armstrong presented a graphical analysis using a comparison of hazard ratios (a statistical tool that measures survival benefit) to show that some trials failed to show a significant progression free survival advantage, yet still ended up prolonging life, and were subsequently approved by the FDA. Examples where this happened include Dendreon’s sipuleucel-T (Provenge) and and a randomized Phase II trial of the immunotherapy Prostvac, which is in Phase III testing currently.

Armstrong also showed the reverse holds true, i.e. trials may show a significant ability to keep tumors from growing, yet ultimately fail to help patients live longer. Prostate cancer trials with … Next Page »

Pieter Droppert is a management consultant, lawyer, science writer and editor of the Biotech Strategy Blog (http://biotechstrategyblog.com) on science, innovation and new product development in the pharma & biotech industries. Follow @3nt

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