Prostate Cancer Drug Winners and Losers at ASCO GU

2/15/13Follow @3nt

The latest clinical research in prostate cancer is being presented at the American Society of Clinical Oncology Genitorinary Cancers Symposium (ASCO GU) in Orlando, FL. Presentations started yesterday, and run through tomorrow, but here’s some quick commentary on three of the early “winners” and “losers” in the oral presentations.

Winners

San Francisco-based Medivation (NASDAQ: MDVN):

Medivation’s enzalutamide (Xtandi) dominated the poster session with several abstracts. Dr. Howard Scher, of Memorial Sloan-Kettering Cancer Center in New York, gave an oral presentation on one of them: a retrospective, unplanned post-hoc analysis of the Medivation’s Phase 3 AFFIRM trial data that was the basis for enzalutamide’s FDA approval last year. This new analysis of the trial explored the relationship of corticosteroid use to survival. The data was first presented at the European Society of Medical Oncology (ESMO) 2012 meeting in Vienna last year.

Scher concluded that “baseline use of corticosteroids was associated with inferior overall survival” and “enzalutamide improved overall survival independent of baseline use of corticosteroids.”

Given the fact that Medivation’s primary competitor, Johnson & Johnson’s abiraterone (Zytiga) needs to be given in combination with corticosteroids, and many urologists don’t like giving immune-suppressing steroids because of their side effects, it’s perhaps not surprising to see why Medivation decided to have a closer look at impact of corticosteroids.

As Dr. Scher noted, however, these data are from a retrospective analysis of a trial that was designed to ask other questions, so the true impact of corticosteroids on survival will have to be confirmed in a different, prospective clinical trial. In providing context, the discussant Dr. William Oh of Mt. Sinai Hospital in New York noted that he thought the patient population on steroids was actually “much sicker” and that “maybe steroids are actually good” in the treatment of prostate cancer that has spread after the standard chemical castration treatment.

Dr. Oh also raised the provocative question, “so are steroids bad, or just used in bad situations?” The answer is we don’t know. I was left with the impression that Medivation maybe was trying to be a bit too clever in slicing the data in this way to gain a commercial advantage. The question of whether steroids are helpful in the treatment of prostate cancer is, however, worth testing in well-controlled, randomized clinical trials.

Sally Church, PhD, my colleague at Icarus Consultants, has an interview on Pharma Strategy Blog with Professor Bertrand Tombal of Université catholique de Louvain (UCL), Cliniques universitaires in Saint-Luc, Brussels, Belgium about another Medivation poster of note, the Phase 1 data for the early use of enzalutamide in prostate cancer patients who haven’t yet gotten the standard chemical castration therapy. Here, enzalutamide could potentially replace generic bicalutamide in what is a large market segment.

San Diego-based Aragon Pharmaceuticals:

The “son of Medivation” compound, or ARN-509 as it is known, is a second-generation androgen receptor antagonist, which works to stop tumors from acquiring the testosterone they need to grow and spread. This compound, like Medivation’s enzalutamide,came out of the UCLA work of Charles Sawyers and Michael Jung. San Diego-based Aragon Pharmaceuticals noted in a press release earlier this year that they had achieved a victory in the ongoing intellectual property dispute with Medivation over ownership of rights to ARN-509. That dispute remains ongoing, since Medivation is likely to appeal the decision, but investor funding of Aragon is now driving clinical trials progress.

Dr. Matthew Smith of Harvard Medical School and Massachusetts General Hospital presented results of an early clinical trial (Phase 1/II) for ARN-509 in men with high risk castration-resistant prostate cancer that hasn’t yet spread. This data was first presented at ESMO 2012 last year.

An impressive waterfall plot was presented. Dr. Smith noted that “at 12 and 24 weeks, 91 percent of patients had a greater than 50 percent PSA decline from baseline.” He concluded that the data supports the “further development of ARN-509 for prostate cancer.”

The extent to which ARN-509 may be a competitor to 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.

Loser

New York-based Bristol-Myers Squibb (NYSE: BMY).

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.

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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