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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.