The treatment of advanced prostate cancer has seen dramatic progress since the original introduction of hormonal therapy to replace orchiectomy (surgical castration). There have been many recent advances that have significantly changed the landscape of prostate cancer treatment. Historically the management of metastatic prostate cancer has involved either medical or surgical testosterone blockage, which is called androgen deprivation therapy.
This approach has been used until the prostate cancer becomes resistant to androgen deprivation, after which the cancer is considered ‘castration resistant’.
Much of the focus in recent years on the treatment of prostate cancer has been in this setting. Since the FDA approval of Abiraterone (Zytiga), an androgen synthesis inhibitor, in 2008, a number of new agents have been approved and incorporated into the treatment. These include Enzalutamide (Xtandi), Sipuleucel-T (Provenge), Radium-223 (Xofigo), and chemotherapy. As the arsenal has expanded, so has the success in treating metastatic prostate cancer with significant improvements in overall survival with the above interventions. One of the biggest dilemmas has been the sequence those therapies, especially when to treat with chemotherapy. With the development of Zytiga and Xtandi, chemotherapy use has until recently been pushed back in the order of treatment. New clinical trials have given a lot of information to help answer the question of sequence.
The CHAARTED trial was a large phase 3 randomized clinical trial published in the New England Journal of Medicine and initially presented in the 2014 ASCO Annual Meeting. This trial showed that the addition of Docetaxel (Taxotere) chemotherapy to standard hormone therapy extended survival by more than one year in men with newly diagnosed, hormone-sensitive metastatic prostate cancer, when compared to hormone therapy alone. A pre-planned six cycles of Taxotere were given in the trial with an oral steroid Prednisone, in combination with androgen deprivation therapy. Overall survival was on an average 14 months longer that the group that received androgen deprivation alone, and the risk of death was decreased by almost 40%. This was especially true in men with extensive metastatic disease, meaning four or more bone metastases or organ metastases (e.g. liver, lung).
This study was the first large clinical trial to suggest that not only should chemotherapy be used early in the course of treatment, but that it was actually better not to wait until the cancer has lost sensitivity to hormone blockade.
Initial results of the STAMPEDE trial were presented at the 2015 ASCO Annual Meeting. This trial is the largest randomized clinical trial conducted to date for management of advanced prostate cancer. While the trial aims to answer multiple different questions, the recent results focused on one component of the trial, in which over 1000 men with either metastatic or high risk prostate cancer were randomly assigned to receive either standard hormonal therapy plus Taxotere chemotherapy or hormonal therapy alone.
As seen in the CHAARTED trial, the addition of chemotherapy to hormone therapy showed a nearly one year improvement in overall survival. The impact of chemotherapy was the most pronounced in those patients with metastatic disease (as compared to non-metastatic high risk), with a reported difference of 22 months in overall survival.
Based on these practice-changing trials men with newly diagnosed metastatic hormone-sensitive prostate cancer should be offered chemotherapy with Taxotere in addition to hormone therapy as an upfront treatment. In addition there is mounting evidence that men with high risk non-metastatic disease might benefit from chemotherapy as well. Long term results of two trials, including the TAX 3503 study and the PUNCH trial will give additional clarity to that point.
These studies continue to add to the exciting progress that has been made in the treatment of prostate cancer. As with all cancer treatments it is important that both the risks of therapy as well as the potential rewards be considered before choosing a specific plan.