The continuing search for impactful chemotherapies in HRPC

In March this year it was announced that the combination of bevacizumab (Avastin) with docetaxel and prednisone had no benficial impact (in a large Phase III trial) on the overall survival of men with hormone-refractory prostate cancer (HRPC) compared to docetaxel + prednisone alone. There are, naturally, hopes that the outcome might be different if one adds a third drug into the mix.

Ning et al. have reported data from a single-arm, Phase II trial in which they combined bevacizumab with docetaxel and thalidomide.  They had previously shown that this combination was highly active in mice.

Unfortunately the authors do not give the total number of patients treated with this combination of drugs. (We assume it was not a large number.) They state the following results in treatment of men with HRPC:

  • 90 percent of patients had declines of ≥ 50 percent in their PSA levels.
  • 88 percent of patients achieved a PSA decline of ≥ 30 percent within the initial 3 months of treatment.
  • Median time to disease progression was 18.3 months.
  • Median overall survival was 28.2 months (as compared to a predicted survival of 14 months, based on the Halabi nomogram).
  • Toxicities were “manageable,” but all patients developed grade 3/4 neutropenia.

The research team concludes that “addition of bevacizumab and thalidomide to docetaxel is a highly active combination with manageable toxicities.”

The “New” Prostate Cancer InfoLink expects that we will continue to see many small trials of this type as clinical researchers use varied combinations of approved agents in an attempt to improve on the survival benefits of docetaxel-based chemotherapy. However, we are concerned that: (a) the actual survival benefits that may be offered by such combination chemotherapies are likely to be small, and (b) any such small survival benefits are likely to come at a significant cost in terms of toxicities of the combinations of agents being used. (Just as an example, Grade 3/4 neutropenia, albeit “manageable,” is by no means a mild side effect.)

While we would not wish to discourage researchers from seeking the most effective combinations of available therapeutics, nor to discourage patients with progressive HRPC from participation in such trials, we would also want to strongly encourage clear communication of the potential risks as compared to the potential benefits to all patients considering participation in such trials. Chemotherapy has a long history in the treatment of HRPC, but after nearly 40 years we still know of only one drug combination (docetaxel + prednisone) that has clearly demonstrated a survival benefit in a large, randomized, controlled Phase III trial. The track record of chemotherapy in prostate cancer, to date, has been less than stellar.

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