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 Roche/Genentech’s bevacizumab (Avastin), Spectrum Pharmaceuticals/GPC Biotech’s satraplatin and Pfizer’s sunitinib (Sutent) are examples of this. Amgen recently had problems convincing the FDA’s cancer drug advisory committee that a measurement of bone-metastasis free survival—the time it takes for cancer to spread to the bones—was a meaningful study goal in the absence of an overall survival benefit.

Armstrong’s conclusion was that survival “remains the gold standard” and that, “Progression-free survival (radiographic or PSA or composite) has not been demonstrated as a surrogate despite associations with OS.”

Companies designing clinical trials should take note. There’s a lot of science that still needs to be worked out to help us understand why delays in the spread of tumors don’t always lead to longer survival times. According to Armstrong, “the relationship of an endpoint to OS depends on the mechanism of action of the drug under evaluation.”

3. Overcoming resistance may require novel combinations and appropriate sequencing of prostate cancer drugs

Patients can develop resistance to advanced prostate cancer drugs such as abiraterone and enzalutamide. In other words, with time the drug becomes less effective, and ultimately the disease progresses. A visual metaphor for adaptive resistance is to think of a drug blocking several Manhattan cross-streets in NYC, preventing the cancer from moving cross-town. Ultimately, the cancer finds an alternative route. All the drug has done is delay the cancer, slow down disease progression, but the cancer has not been cured.

At ASCO, a poster presentation by Elena Ileana and colleagues from the Institut Gustave Roussy in France showed possible cross-resistance between abiraterone and enzalutamide. They found that:

“Abiraterone combined with prednisone yields limited activity in patients with metastatic castration-resistant pretreated by docetaxel and MDV3100” [now known as enzalutamide].

This means that sequencing of different therapies will become an important consideration once more data is available in order to ensure optimal effectiveness of prostate cancer drugs. The development of cross-resistance may potentially lead to enzalutamide being preferred in the pre-chemotherapy setting with abiraterone used in the post-chemotherapy setting.

The sample size the French research group looked at was small, only 24 patients on abiraterone. However they showed that only 13 percent of men who had previously received enzalutamide, had a decline in Prostate Specific Antigen (PSA) levels of more than half. This compared to 29 percent in the COU-AA-301 trial for abiraterone, where men had not received enzalutamide in advance.

According to Nima Sharifi, an assistant professor at the University of Texas Southwestern Medical Center, who discussed the poster at ASCO 2012, “the results probably indicate that there is an overlap in mechanisms of resistance to abiraterone acetate and MDV3100 [enzalutamide].”

Sharifi discussed the need for “more data on cross resistance between enzalutamide and abiraterone”, and the “need to develop biomarkers of response/resistance to either versus both agents in order to better inform treatment selection.”

For companies bringing new prostate cancer drugs to market, they will face the challenge of not only determining how effective their drug is against the new standards of care, but also whether other drugs may impact effectiveness as a result of cross-resistance. The optimal sequence of prostate cancer drugs and new combinations for increased effectiveness is a topic we will likely see more of at future medical meetings.

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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