The approval of Provenge has once again brought to the forefront the very important questions about the proper timing of treatments as well as the issue concerning how to combine therapies to maximize survival. We have, although there numbers are limited, different treatments that are used for the treatment of advanced prostate cancer, but we are at a loss of when is best to use which treatment and can combining any treatment yield an even better survival advantage. Additionally, looking into the near future, we will hopefully be adding a number of additional treatments to our approved list, so where do we place these drugs in the sequence of treatment?

The big, over hanging question is in what order we should use the available treatments and will combining any of these treatments extend survival even longer than when the treatments are used alone, as we do today?

Until the approval of Provenge, Docetaxel plus prednisone (D+P) was the standard treatment for men with castration-resistant prostate cancer (CRPC). Now, we are faced with the question, where in the treatment order do we use new drugs (i.e. provenge) and if we combine them with other treatments, new and existing, will it extend survival even longer?

A small phase I trial performed by Figg et al. combined D+P with different doses of ketoconazole (Keto), an unapproved drug often used as a second line hormone treatment. The trial enrolled 42 men who had metastatic, castrate resistant prostate cancer (mCRPC) who were treated with weekly D+P for 3 of every 4 weeks plus a daily dose of Keto.

The researchers studied a variety of different doses of Keto and D+P. Weekly D+P doses ranged from 5 to 43 mg/m2, with starting doses of 600, 800 or 1,200 mg of keto daily. They found that PSA levels were lowered by 50 percent in 26/42 men (62 percent). They also found that in 7/25 men (28 percent) who had soft tissue mets had a partial response to therapy.

They also found that the median overall survival of the men was 22.8 months and there was a significantly greater survival in men who were D+P naïve than in men who had already been treated with D+P (36.8 vs 10.3 months, p = 0.0001).

There were a number of morbidity issues faced by the men in the trial; with the most frequent being anemia, edema, fatigue, diarrhea, nausea, sensory neuropathy, and elevated liver function tests.

The researchers also found that there was a correlation between D+P clearance and Keto. 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 researchers conclude that combination regimens using 600 mg keto daily were well tolerated and that the maximum tolerated dose of D+P in combination with keto was 32 mg/m2. They go on to suggest that this combination has significant anti-tumor activity in mCRPC.

Now we need to see if clinicians pick up on these findings. This study should lead to changes in the schedule and dosing of treatment regimes used to treat mCRPC.

This study does raise the serious question about how we combine treatments and how we time treatments in the disease process. There are potential treatments in addition to Provenge on the horizon and they, as well as Provenge, will need to be properly placed into the puzzle, how to best treat men with mCRPC so as to maximize their survival.

This remains a huge question, but an important one if we are to maximize the survival of men with mCRPC.

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 S, Zhu W, Chen X, Ajiboye AS, Steinberg SM, Price DK, Wright JJ, Parnes HL, Arlen PM, Gulley JL, Dahut WL.

PMID: 20399458

Joel T Nowak, MA, MSW