Problems with enrollment into ongoing Phase III trials of new drugs for men with mCRPC?


Has the clinical success of some new drugs started to affect enrollment in trials of others for advanced forms of prostate cancer?

Back in November 2010, Millennium announced the initiation of two large, multi-center, randomized, double-blind, Phase III trials designed to test the effectiveness and safety of a drug known as TAK-700 (in combination with prednisone) in the treatment of two slightly different groups of men:

  • Men with chemotherapy-naive, metastatic, castration-resistant prostate cancer (mCRPC), i.e., men who had never been treated with docetaxel (Taxotere®)
  • Those with mCRPC who had progressive disease after or while being treated with a docetaxel-based chemotherapy regimen

In each of these two trials, men who did not get randomized to treatment with TAK-700 + prednisone get treatment only with a placebo + prednisone (just as in the trial of abiraterone acetate that showed an overall survival benefit for that drug).

Since November 2010 we have seen the approval of three new drugs for late stage prostate cancer: cabazitaxel, sipuleucel-T, and most recently abiraterone acetate. In the near future we can also hope to see the approval of radium-223 and MDV3100. This means that potential candidates for participation in the Phase III trials of TAK-700 may, instead, have been deciding to seek treatment with one of the three agents already available on the market. As of last week, they may also be able to enroll in the compassionate use study of radium-223. At some point in the near future, we can expect to see the initiation of a compassionate use study of MDV3100 too.

One does have to ask oneself why a patient would want enroll in a trial of a drug like TAK-700 — also known as ortoronel — for which there is limited information on effectiveness and safety. Such men already have the option of taking other drugs for which there are detailed data on effectiveness and safety. If they chose to participate in the TAK-700 trials, there is a 50 percent chance that they would get a placebo as opposed to the active drug!

On the other hand, the two trials referred to above are critical to the ability to determine whether TAK-700 + prednisone will be another useful addition to the clinical armamentarium for the treatment of late-stage prostate cancer.

TAK-700 is one of the last drugs that will be ever be tested against a placebo in a Phase III trial for the first-line treatment of chemotherapy-naive or docetaxel-refractory mCRPC. Others that are also being tested in comparable Phase III trials are ipilimumab and tasquinimod. In the future, trials of new drugs in the management of mCRPC are necessarily going to require head to head comparison with another drug or careful selection of men for clinical trials who have failed treatment with at least two or more drugs. (As an example, the proposed Phase III trials of cabozantinib, also known as XL184, are going to be in men with more advanced forms of disease who have already been treated and progressed after the use of docetaxel and abiraterone acetate, in no particular order.)

Clearly, the potential development of TAK-700 appears to have been impacted by the successful development of other agents. Millennium is still encouraging enrollment of patients into the two trials referred to above, and The “New” Prostate Cancer InfoLink sincerely encourages appropriate patients to enroll in these trials as well. It would be a great pity if we could never find out whether drugs like TAK-700 were valuable in advanced prostate cancer, but if Millennium cannot complete enrollment in the two trials into which they have now invested millions of dollars, it is hard to see how they could decide to “start again” and consider enrolling patients into new trials designed to assess the potential of TAK-700 in men who had failed both docetaxel and abiraterone or some other drug combination.

This is, of course, a well understood risk associated with drug development … that a competitor will beat you to the market and make it difficult or impossible to complete your own trial or set the bar so high that your drug cannot compete. On the other hand, from the patient point of view, TAK-700 is slightly different to abiraterone acetate and MDV3100. It may be that some men will respond well to this drug but do not respond as well to abiraterone or MDV3100. If TAK-700 (and ipilimumab, and tasquinomod) are effective and safe in the treatment of prostate cancer, we need to know this … and we will only know this if their sponsors are able to complete the current, ongoing Phase III trials.

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