Appropriate sequencing of treatments among men with advanced prostate cancer

Whether a man is initially diagnosed with metastatic prostate cancer or progresses to have metastatic disease over time (after failure of standard first-line therapies), sooner or later they are all going to need — in consultation with their doctors — to decide on “the best” way to manage their progressive disease through sequential or concurrent use of a number of recently approved agents (always assuming that cost and access are not determining factors). The problem is that — at least at present — there is no really appropriate way to determine what (if anything) is most likely to have the greatest effectiveness in an individual patient.

A case report published recently by Colbourn offers an excellent example of the complexities of this problem. Colbourn describes the following sequence of therapeutic interventions in a man of 58 years, initially diagnosed with an advanced form of prostate cancer in 2006:

  • Initial management with radical prostatectomy followed by androgen deprivation therapy (but his PSA continued to rise post-treatment).
  • Enrollment in a clinical trial of HE3235 for 6 months (but his disease subsequently progressed again).
  • Treatment with docetaxel-based chemotherapy for 4 months (followed by palliative radiation therapy).
  • Treatment with cabazitaxel-based chemotherapy, initiated in October 2010 (at which time his PSA level was > 5,400 ng/ml).

This sequence of treatments makes perfectly reasonable sense at a time when sipuleucel-T, abiraterone acetate, and enzalutamide were not approved therapeutic agents (although the patient may have been eligible for enrollment in the one or more clinical trials of abiraterone acetate or enzalutamide or other agents during this time frame).

What came next, however, was not exactly predictable:

  • The patient’s condition stabilized within weeks.
  • His PSA level demonstrated a progressive decline.
  • Continued cabazitaxel-based therapy allowed him to come off pain medications and to resume his normal activities.
  • As of January 2012, after 16 cycles of cabazitaxel, his PSA had declined by > 80 percent (to 994 ng/ml).

Colbourn further reports that the patient tolerated cabazitaxel well; needed only occasional dosing with myeloid growth factors for management of neutropenia; and experienced only mild diarrhea.

Why did this man respond so well to cabazitaxel, after relatively rapid failure in response to other forms of therapy? How can we optimize the likelihood that other such men could be identified with accuracy, such that cabazitaxel could be administered early? Is it possible that this man, if treated with cabazitaxel immediately after his radical prostatectomy, might have shown an even better response to treatment?

These are the sorts of questions that we need to be able to answer if we are going to be able to truly individualize treatment in the most appropriate manner for men with clinically significant prostate cancer. And, as we bring more products through clinical trials and make them available for the treatment of progressive prostate cancer, the pressure to be able to know who is most likely to respond best to specific combinations of drugs (or just individual drugs as in this case study) is only going to increase.

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