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Posts tagged ‘ESMO 2012 Prostate Cancer’

ESMO 2012 ODM-201 Prostate Cancer PosterAt the 2012 European Society for Medical Oncology (ESMO) meeting in Vienna today, the first published clinical data for a new second generation anti-androgen (ODM-201) was presented. Company representatives inform me that the poster will be available on the Orion Pharma website in a few days. (Update Oct 9: it is now available, but all the text on the PDF of the poster available for download appears to have been intentionally blurred to make it unreadable!)

What makes ODM-201 interesting? The company claimed on their poster, “it is a uniquely designed AR antagonist” yet citing confidentiality reasons refused to answer questions about it or offer a comparison of their drug to other second-generation androgen receptor (AR) antagonists ahead of them in development such as ARN-509, or enzalutamide (Xtandi), which was recently approved in the United States. This perhaps reflects their inexperience as an oncology drug development company, and was a missed PR opportunity.

What the Orion Pharma poster does say is that ODM-201 has “negligble brain penetrance” in nonclinical models. If there are CNS problems with enzalutamide then this would be a major potential advantage, but a more important question in my view is whether ODM-201 has activity against splice variants? The company declined to answer.

Joan Carles, MD PhD (Vall d’Hebron, Barcelona) was the poster discussant and summed up the phase 1 dose escalation trial with 18 patients by summarizing the strengths and weaknesses of the data presented for ODM-201:

Strengths

  • High efficacy
  • Well tolerated
  • Linear pharmacokinetics

Weakness

  • Few patients

We will have to wait for more trial results with ODM-201 and more information on its mechanism of action before it’s potential can be properly evaluated, but at first glance it appears to offer promise.

However, Orion Pharma are seeking to enter a very busy and competitive prostate cancer market. Some of the challenges it faces will be:

  • Which agent to use as a comparator when it moves into randomized trials?  The days of placebo controlled trials in advanced prostate cancer appear to be now over, and most likely it would have to compare itself against enzalutamide if this is the standard of care it will be competing against.
  • Will it need to combine with other agents to be successful? The future is now moving towards combinations. Presuming ODM-201 continues to show promise, will Orion Pharma combine ODM-201 with another novel agent e.g. a PI3K inhibitor? Will they have the courage to do a novel-novel phase 2 combination trial?

The prostate cancer landscape just got even busier with the arrival of ODM-201 on the scene and it will be interesting to watch the drug development strategy of Orion Pharma in partnership with Endo Pharmaceuticals, who have a pain and urology franchise.

I certainly look forward to seeing more data on ODM-201 at future medical meetings and evaluating it against enzalutamide as more data becomes available.

One of the late-breaking abstracts (not yet published) that I am looking forward to at the forthcoming annual Congress of the European Society for Medical Oncology (ESMO 2012) in Vienna is on ODM-201 (Orion Pharma):

LBA25-PR:  ARADES trial: A first-in-man, open-label, phase I/II safety, pharmacokinetic, and proof-of-concept study of ODM-201 in patients (pts) with progressive metastatic castration-resistant prostate cancer (mCRPC)

ODM-201 is a new antiandrogen from Finnish company, Orion Pharma, and is being developed in partnership with Endo Pharmaceuticals (NASDAQ: ENDP).

Orion Pharma LogoIn a corporate presentation, Orion Pharma describe ODM-201 as:

  • Potentially best-in-class antiandrogen
  • Does not enter brain in preclinical models
  • No testosterone increase in animal models
  • Well tolerated

“We are studying and developing an anti-androgen with qualities that currently cannot be found in any of our or our competitors’ drugs”

says Mika Mustonen (@MikaMustonen), Head of Oncology, Research and Development at Orion in an article, “Pursuing a targeted drug for prostate cancer” published by the company. Mustonen says:

“The research on our new drug candidate, ODM-201, suggests that we may be able to provide patients with a new alternative for the treatment of prostate cancer.”

Of note, is Orion’s focus on biomarkers, which may help predict which patients are more likely to respond to the therapy. According to Mustonen:

“Biomarkers increase the chance of success.  By following them we can study topics that have not been considered before in this type of research.  We can predict different phases of the disease, survey any safety risks associated with the drug and find out what kind of patients benefit most from the drug.”

At ESMO 2012 (Twitter hashtag #ESMO12) I expect we will hear preliminary data from the ARADES 3104001 phase 1 dose escalation study (NCT01317641) with ODM-201.

According to clinicaltrials.gov this multicenter, non-randomized clinical trial is being undertaken at sites in Finland, Czech Republic, France, United Kingdom and the United States.

After 12 weeks in the phase 1 dose escalation study, patients with stable disease can continue treatment in a phase 2 extension study on the safety and tolerability of ODM-201 (NCT01429064).

As of May 2012, Orion Pharma reported that the ARADES 3104001 phase II expansion component had 105 patients enrolled, with 3 dose levels to be expanded.

Company senior management have told me they “are very excited about the ODM-201 data,” to be presented at ESMO. I have not seen the data, but presume the results will be positive. After all, company executives don’t get excited about negative data!

Is there a market for a new antiandrogen?

Although Medivation are first to market with their androgen receptor (AR) inhibitor, enzalutamide/MDV3100 (Xtandi) that does not mean that other companies will not be able to make in-roads into the market with cheaper or more effective AR antagonists.

In a Pharma Strategy Blog interview with Sally Church, Dr Charles Sawyers noted that Aragon’s ARN-509 (another AR inhibitor in development) is “more potent” than enzalutamide and “might produce a higher percentage of responders or longer duration of response.”

Medivation recently announced that enzalatumide is available in the United States for patients with metastatic castration resistant prostate cancer previously treated with docetaxel.

At a price of $7,450 a month, however, Xtandi is considerably higher than Johnson & Johnson’s Zytiga.  This aggressive premium pricing strategy opens the door to competitors who may offer equally effective, but less expensive drugs.

The prostate cancer market remains a dynamic one and very much one to watch over the next few years.

I look forward to learning more about ODM-201 at ESMO 2012.

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At the 2012 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Oliver Sartor, Professor of Cancer Research and Medical Director of the Tulane Cancer Center in New Orleans told attendees in the educational session on castration-resistant prostate cancer (CRPC) that he was tired of being asked the question of what is the optimal sequence for new advanced prostate cancer drugs?

ASCO 2012 CRPC Prostate Cancer Education SessionThere is “No data,” Sartor told the ASCO 2012 audience. As a result he recommended the use of less toxic therapies first and that patients be involved in the decision making. Not quite the guidance the audience perhaps hoped for.

Sartor is, however, correct that we don’t yet have the data – the clinical trials have yet to be done that will answer the question of what is the optimal sequencing of prostate cancer drugs?

The approval of abiraterone acetate (Zytiga®) for the treatment of men with advanced prostate cancer, post chemotherapy, and the expected approval of enzalutamide (formerly MDV3100) and radium-223 (Alpharadin) have focused attention on sequencing and combination options.

A poster at ASCO 2012 showed that cross resistance may occur between abiraterone and enzalutamide, suggesting that if resistance to one develops it may lower the efficacy to the other if given subsequently. More data and research is needed to validate this finding and understand how resistance develops.

Reciprocal feedback between the PI3-Kinase and androgen receptor (AR) signaling pathways means that blocking the androgen receptor may stimulate the PI3K pathway and vice versa, leading to the tumor trying to ensure its survival. This is particularly important in prostate cancers that have the PTEN tumor suppressor gene, the result is that the targeting of both PI3K and the AR to avoid crosstalk may be required.

The scientific rationale for combining enzalutamide with a PI3-kinase inhibitor was discussed on Pharma Strategy Blog in Sally Church’s video from the 2011 American Urological Association annual meeting. Clinical trials are being planned to investigate the use of PI3-kinase inhibitors in prostate cancer.

I have written more from ASCO 2012 about the emerging challenges in prostate cancer drug development in a guest post published on Xconomy.  Many thanks to Luke Timmerman, National Biotech Editor, for the opportunity to contribute.

Hopefully, there will be more insights available at ESMO 2012 later this year and at ASCO next year on prostate cancer drug resistance, optimal sequencing and the benefits that combinations therapies may offer.

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