When to Use A Treatment & What Drugs Should Be Combined?
The recent approval of six new drugs for the treatment of prostate cancer (Xgeva, Provenge, Zytiga, Xtandi, Xofigo and Jevtana) raises an important question regarding the proper sequence and timing of treatments, as well as the efficacy of combined treatments in order to maximize overall survival.
An example is a small phase I trial which combined docetaxel (Taxotere) and prednisone with different dose levels of Ketoconazole (Keto). This trial enrolled 42 men with metastatic, castrate resistant prostate cancer (mCRPC). They were treated with docetaxel and prednisone (D+P) three of every four weeks plus a daily dose of Keto. The researchers studied a variety of different Keto doses and docetaxel plus prednisone (D+P). They found that by combining the therapies, PSA levels were lowered by 50 percent in 62% of the men and that 28% of the men with soft tissue metastases had a partial response to therapy.
They also found that the median overall survival of the men was 22.8 months, but by altering the timing of the treatments they found that there was a significantly greater survival in men who were D+P naïve than in men who had already been previously treated with D+P (36.8 vs 10.3 months). There was a correlation between Keto and D+P clearance (the time it takes for your body to rid itself of the drugs). Keto increased docetaxel exposure 2.6-fold at a Keto dose of 1,200 mg daily, 1.6-fold with 800 mg daily, and 1.3- to 1.5-fold with 600 mg daily.
The trial concluded that a combination regimen using 600 mg Keto daily was well tolerated and that the maximum tolerated dose of D+P in combination with Keto was 32 mg/m2. They also suggested that this combination has significant anti-tumor activity in men with castrate resistant prostate cancer. (Citation: J Urol. 2010 Jun;183(6):2219-26; A phase I clinical study of high dose ketoconazole plus weekly docetaxel for metastatic castration resistant prostate cancer.; Figg WD, Woo 5, Zhu W, Chen X, Ajiboye AS, Steinberg SM, Price DK, Wright II, Pames HL, Arlen PM, Gulley JL, Dahut WL. -PMID: 20399458)
In terms of combining Provenge with other CRPC treatments, its manufacturer, Dendreon, is now running new clinical trials designed to evaluate the use of Provenge at different times during prostate cancer disease progression and with different drug combinations like ADT, Yervoy and Zytiga.
All these studies deal with the all-important question of how to combine and how to sequence treatments in disease process. How we properly order and combine treatments to maximize our survival remains a great and as yet unanswered question. (http://advancedprostatecancer. net/?p=1677)