Orteronel active as “switch” maintenance therapy after docetaxel chemotherapy

According to a presentation given at the European Cancer Congress, currently ongoing in Vienna, Austria, a small, recently completed Phase III trial has shown that orteronel (TAK-700) might have had some value in treatment of late stage prostate cancer after all.

In two earlier Phase III clinical trials (see here and here for details), orteronel had failed to demonstrate a survival benefit in the treatment of men with progressive, metastatic, castration-resistant prostate cancer (mCRPC). The company then terminated development of orteronel in the treatment of mCRPC (on June 19, 2014).

A media release from the European Society for Medical Oncology (ESMO), issued on Saturday, has now described a presentation of data from another Phase III trial, given by a representative of the Swiss Group for Clinical Cancer Research, in which orteronel showed “promising activity” as “switch” maintenance therapy in men with mCRPC and non-progressive disease following first-line docetaxel-based chemotherapy.

Switch maintenance therapy in men with mCRPC is based on the idea that after treatment designed to put a patient with advanced disease into stable remission, it may be possible to extend the quality of that remission over time (although not necessarily the patients’ overall survival) through the use of some other form of treatment.

In this trial, 3 to 6 weeks after completion of docetaxel-based chemotherapy, patients with stable disease were randomized to treatment with either orteronel plus best supportive care (BSC) or to a placebo + BSC. The patients were then followed until they died or until there was a combination of at least two other outcomes indicative of disease progression, including radiographic, clinical or biochemical (PSA-based) progression. Time from randomization to either death or evidence of at least two of these other forms of progression was defined as “event-free survival” or EFS; this was the primary endpoint of the study.

Here are the study results as reported in the media release:

  • Average (median) patient follow-up was 17 months.
  • Average (median) EFS was
    • 8.5 months in the orteronel + BSC cohort
    • 2.9 months in the placebo + BSC cohort
  • Patients in the orteronel + BSC arm exhibited a significant improvement in EFS, as defined by
    • A hazard ratio [HR] of 0.32
    • A p-value of 0.001
  • PSA decreases of > 50 percent were observed in
    • 57 percent of patients treated with orteronel + BSC
    • 4 percent of patients treated with a placebo + BSC
  • Time to biochemical (PSA-based) progression was
    • 6.5 months in patients treated with orteronel + BSC
    • 1.8 months in patients treated with a placebo + BSC
  • Time to radiographic progression was
    • 8.5 months in patients treated with orteronel + BSC
    • 2.8 months in patients treated with a placebo + BSC
  • During treatment, adverse events were reported in
    • 61 percent of orteronel + BSC patients
    • 83 percent of placebo + BSC patients
  • Higher, but manageable, levels of toxicity were observed in the orteronel +BSC arm of the trial.

However, it has to be made clear that this was a very small Phase III trial. It was only ever intended to enroll 96 patients, and, because Takeda decided to terminate the development program for orteronel, only 47 of those patients were actually enrolled, with 23 being tandomized to orteronel + BSC and 24 to a placebo + BSC.

However, the study investigators note that this appears to be the first trial to demonstrate the efficacy of an active pharmaceutical agent as switch maintenance in men with mCRPC. They went on to suggest that the concept of maintenance therapy after disease stabilization warrants further research in men with mCRPC.

3 Responses

  1. An interesting but not surprising finding. Of course more research has to follow. In the US, SWOG’s S1216 is still recruiting with a recent modification due to standard of care changes that were brought about by the E3805 (CHAARTED) trial. S1216, for which I have been co-authored, is a trial testing the use of leuprolide acetate with orteronel vs. leuprolide acetate with bicalutamide. At the time of the trial design this was testing the standard of care versus the trial arm. Once E3805 showed excellent performance in the patients designated for S1216 it became necessary to allow docetaxel and prednisone with either arm as a standard of care. Perhaps Takeda will find a solid reason to release the TAK700 product after that trial. TAK700 is still under investigation and no results are available at this time. I will be at SWOG in Chicago tomorrow with full closed door discussions. Thanks for this update. It will come in handy Wednesday.

  2. My husband was on TAK 700 from December 20, 2012, to April 19, 2013. He was not sufficiently monitored by an expert; he was monitored by junior doctors.

    It was a savage trial. His body came out in a terrible rash and then in blisters that became hard brown skin. His face was swollen beyond recognition. He was taken off the drug because of the effects it had on his bowel movements.

    On the first Thursday in June he had a bone scan before going back on TAK 700 on the following Monday. The cancer had gone to his bones, and thereafter to other parts of his body.

    He died in July 1, 2013. He was born 12 Dec.1952.

    TAK 700 was a horrific experience for him. It was toxic to the core. I have been thinking of it over the weekend and am very surprised it is in the news again.

    My husband loved life and would have done anything to stay alive. I often wonder what his remaining years would have been like without this savage drug.

    I miss every moment, every breath I take.

  3. Dear Mrs. Gallagher:

    I am very sorry to hear about your husband’s experiences on TAK 700.

    I want to assure you that, as far as I am aware, no one is even thinking about trying to bring TAK 700 “back to life”. The original developer stopped all further study of this drug some time ago.

    The point being made by the researchers who reported these data is that a drug that could be used as long-term maintenance therapy in the management of men with advanced prostate cancer who were in remission after initial treatment could have considerable potential value … but it would need to have a much better safety profile than TAK 700.

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