Prostate Cancer Drug Winners and Losers at ASCO GU
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enzalutamide remains to be seen. There are several other second generation androgen receptor antagonists in development, and they will all have to run clinical trials to show they are indeed superior to enzalutamide to support their claims. The days of doing placebo controlled clinical trials in advanced prostate cancer are over. Now that there are effective treatment options available, it would be unethical to give men an inactive drug.
Dr. Oh, in his discussion of the ARN-509 presentation, asked the question, ”Will more potent AR inhibition improve clinical outcomes?” In other words, will next generation compounds that may have greater potency, lead to men actually living longer? We don’t know, but it’s a critical issue that needs to be addressed in future clinical trials. Dr Oh noted that it is too early to say how clinically meaningful the benefits of next-generation androgen receptor compounds may be, but that they may be “incrementally better.”
There is an old, but true saying in pharma marketing, “be the first or be the best.” The future in prostate cancer is most likely to be combination therapies to overcome drug resistance and prolong disease progression. We still have a long way to go in understanding how to sequence and combine new drugs for advanced prostate cancer.
Dr. John Araujo of MD Anderson Cancer Center in Houston, TX presented the final analysis of the Phase 3 READY trial of Bristol-Myers’s dasatinib (Sprycel) as if he were delivering the eulogy to a long-departed friend. This study, which was unfortunately negative, compared the combination of dasatinib plus docetaxel to docetaxel chemotherapy alone in men with advanced prostate cancer. Dasatinib is a BCR-ABL tyrosine kinase inhibitor but also targets Src (pronounced Sark). The drug is FDA approved for the treatment of chronic myeloid leukemia (CML), but Bristol-Myers tested it in prostate cancer after preclinical work suggested that Src is thought to play a role in prostate cancer growth, invasion and metastases.
The trial was a bust, with dasatinib offering no survival benefit in any subgroup of men treated. This well-conducted trial cost Bristol-Myers tens of millions of dollars to run, and shows the perils of rushing into expensive Phase 3 drug development on the back of only a couple of early non-randomized single-arm clinical trials.
Dr. Araujo suggested that dasatinib may have some effect in delaying the time it takes for prostate cancer to spread to the bones—a painful reality for many with the disease— but Dr Oh pointed out that this result might be due to the fact that a large number of patients had not received bisphosphonate treatment.
The study investigators, especially given the promising preclinical and early Phase I/II studies being suggestive of a strong scientific rationale for the concept, clearly did not expect the resounding failure of the READY trial. Additional research is ongoing using genomic and image guided therapy to investigate potential avenues of research.