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How serious ARE the side effects of cabazitaxel?

Posted Jun 14 2010 12:00am

As has been previously mentioned on this web site, cabazitaxel a second-generation taxane has a good chance of being approved some time soon for the treatment of patients with castration-resistant prostate cancer (CRPC) who have already progressed after treatment of docetaxel (Taxotere). However, we have been hearing some expressions of concern about the side effects that may be associated with the use of this new drug.

The relevant clinical trial the TROPIC trial was a Phase III, randomized, double-blind, multi-center study that compared cabazitaxel + prednisone to mitoxantrone + prednisone in men with CRPC who had already progressed after treatment with docetaxel-based chemotherapy.

An article on the Medscape Oncology web site today gives more detail on the concerns that have been expressed. In particular it is worth drawing attention to the following:

  • Exactly how high is the incidence and severity of peripheral neuropathy (numbness in the extremities) associated with cabazitaxel treatment in men with metastatic CRPC?
  • Approximately 5 percent of patients in the cabazitaxel + prednisone arm of the TROPIC trial supposedly died from treatment-related side effects.
  • In the TROPIC study, the rate of grade 3 or higher febrile neutropenia was 7.5 percent in the cabazitaxel + prednisone group and only with 1.3 percent in the mitoxantrone + prednisone group.

All of these issues are specifically addressed in the article on Medscape Oncology referenced above, and we do not intend to go through them point by point here. We would rather focus on something quite different, which is the opportunity being presented to very late stage prostate cancer patients.

Metastatic CRPC kills > 28,000 patients in the USA each year. Once they fail docetaxel-based chemotherapy,these men have no further approved forms of treatment that are known to offer a survival benefit, but some of these patients are healthy, fully functioning individuals. They are entitled to further clinical hope with all appropriate due warnings.

It is quite clear that cabazitaxel when approved to treat metastatic CRPC will probably need to come with some very clear warnings about the risks associated with its use. This is perfectly normal for many, many drugs used in the treatment of late stage cancers. Just look, for example, at the warnings that come on the prescribing information for two of the drugs widely used in the treatment of progressive colorectal cancer: bevacizumab/Avastin and capecitabine/Xeloda .

Unless there is information suggesting that the potential risks associated with use of cabazitaxel are significantly higher than the potential benefits, cabazitaxel should be approved as a treatment for metastatic CRPC and as soon as possible. Physicians and their patients can and will then need to make individual, patient by patient decisions about the use of cabazitaxel in patients who need such chemotherapy. And they should make those decisions with full awareness of all known side effects of cabazitaxel and any known factors that may predispose patients to those risks. But let us be clear … metastatic CRPC is not a mild form of arthritis. Most of these patients are going to die with or from their disease if they cannot receive treatment that delays the progression of that disease.

The benefits of cabazitaxel + prednisone are not huge. Based on the data from the TROPIC trial, cabazitaxel appears to extend survival by an average of about 2.6 months compared to mitoxantrone + prednisone. That means it will do a great deal better than that for some men and a great deal worse for others. But these are men who are running out of options.

Will there be an obligation on medical oncologists to use cabazitaxel with great care and with appropriate supportive medications to minimize adverse events? Of course there will. But the idea that we might not see the approval of cabazitaxel because of its adverse effects seems horrific to The”New” Prostate Cancer InfoLink. Such a decision would (we believe) represent a unique case of a cancer drug showing a clear overall survival benefit in a well-structured, randomized, double-blind clinical trial and then not being approved for the treatment of the patients who need it.

Even if the FDA is really concerned about the potential for serious side effects being associated with wide clinical use of cabazitaxel, there are mechanisms (e.g., the Risk Evaluation and Mitigation Strategies or REMS mechanism) that would allow the FDA to ensure that use of cabazitaxel is limited only to patients who met specific disease criteria and who are fully informed about the relevant risks. The REMS mechanism has already been applied in the approval of a wide spectrum of drugs that come with risks for severe side effects, including the erythropoesis-stimulating agents (darbepoetin/Aranesp and epoetin alfa/Epogen and Procrit) and many other products.

We do need to understand the risks and adverse effects associated with drugs like cabazitaxel. But we have mechanisms in place to monitor and manage these risks. And oncologists have been making such decisions and helping to inform their patients about them for years. The risks cannot be taken lightly but they also need to be balanced against the hope for extended life in appropriately selected patients.

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