Docetaxel in Prostate Cancer -- The Pendulum Swings Back

David Graham, MD


August 31, 2015

It's interesting to look back at the history of therapies for prostate cancer. We have taken advantage of the androgen sensitivity in early prostate cancer for decades. Where we ran into trouble, however, was when prostate cancer originally referred to as "androgen independent" became what is now commonly called "castrate resistant." We had a number of other hormonal therapies, including megestrol acetate and low-dose dexamethasone, but they all have relatively poor response rates and a minimal impact on survival. It was not until 1996 that mitoxantrone, a drug first developed for acute myeloid leukemia, became the first cytotoxic agent to get approval in metastatic prostate cancer. This was despite the fact that the trial, published in the Journal of Clinical Oncology in 1996,[1] did not demonstrate an improvement in overall survival but did show a significant improvement in palliative endpoints such as pain control and analgesic use.

And there we stayed for the next 8 years until the TAX-327 trial was reported in the New England Journal of Medicine.[2] In that trial, docetaxel plus prednisone was compared with mitoxantrone plus prednisone in 1006 men with "hormone refractory" prostate cancer. The use of docetaxel led to an increase in overall survival of 2.4 months, the first time an improvement in overall survival had been attained. The results of this trial led to a US Food and Drug Administration (FDA) indication for docetaxel in metastatic androgen-independent prostate cancer on May 19, 2004.

For the next 7 years, because there was little else to choose, docetaxel was routinely used early in the course of metastatic disease once progression had been seen on primary hormonal therapy. It was not until 2011 that other options even became possible. Results of abiraterone after the use of docetaxel were published that year, showing an improvement in overall survival.[3] One year later, data on enzalutamide after docetaxel also showed an improvement in overall survival.[4] It wasn't much later that trials looking at the use of these agents before docetaxel demonstrated benefit.

The use of abiraterone pre-docetaxel may have showed only a trend in overall survival improvement, but it did lead to a significant prolongation in the time to use of docetaxel and a significant improvement in radiographic progression-free survival.[5] The use of enzalutamide pre-docetaxel also led to a significant prolongation in radiographic progression-free survival as well as a reduction in the risk for death at the time of data cutoff.[6] It should be noted that median survival was not reached or reported in this publication. These two sets of data, however, were sufficient for the FDA to grant pre-docetaxel indications for abiraterone in December 2012 and enzalutamide in September 2014.

This changed the therapeutic landscape significantly. As oncologists, our mindset tends to follow a therapeutic pathway of "most effective and least toxic" first, followed by either more toxic regimens or less effective regimens. There is no doubt that docetaxel toxicities outweigh those of either abiraterone or enzalutamide. As a result, docetaxel started to get pushed back farther in the course of the disease.

That was until the 2014 American Society of Clinical Oncology (ASCO) annual meeting. There, the CHAARTED trial was presented in abstract form; the trial was published in full last month.[7] In this trial, the upfront use of docetaxel with androgen deprivation was found to lead to an improvement in overall survival of 17 months in men with "high-volume disease"—that is to say, visceral metastases or more than four bone metastases with at least one of those being outside the vertebral bodies or pelvis. This was an unprecedented finding in this population.

This was followed with results of the STAMPEDE trial, reported at the 2015 ASCO annual meeting.[8] That trial included men with newly diagnosed prostate cancer that was either metastatic, node positive, or contained two or more of the following features: Gleason score 8-10, stage T3/4, or prostate-specific antigen (PSA) > 40 ng/mL. Also included were men with relapsed disease after surgery or radiation with at least one of the following: a PSA of at least 4 ng/mL and a PSA doubling time of less than 6 months, PSA > 20 ng/mL, node-positive disease, or metastatic disease. In this trial, the addition of docetaxel to standard of care led to an increase in overall survival of 10 months. This benefit was seen in all subgroups but was significantly notable in men with metastatic disease. In those men, overall survival was improved by 22 months. Final publication has yet to occur, and these results must be considered with that in mind.

The impact of these two trials, even though one has yet to reach final publication, is considered by many to be practice-changing. Dr Maha Hussain from the University of Michigan and Dr Howard Scher of Memorial Sloan Kettering Cancer Center had a very interesting point-counterpoint discussion at ASCO on the timing of docetaxel use as of 2015.

In the group of men with metastatic disease, the pendulum of timing for docetaxel use has swung back to earlier than ever. These data strongly suggest that men who can tolerate it should be given docetaxel not at the time of primary hormone failure but along with androgen deprivation at the time of diagnosis of metastatic disease.


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