High-dose ketoconazole + docetaxel for treatment of CRPC?

Docetaxel + prednisone is the current standard treatment for men with castration-resistant prostate cancer (CRPC). However, the survival benefit of this form of treatment is small compared to older forms of therapy.

Figg et al. have now reported data from a small (Phase I) trial that combined docetaxel with different doses of ketoconazole — another, older drug that also has proved impact on the progression of prostate cancer. The trial enrolled 42 patients, all of whom had metastatic, CRPC and who were treated with weekly docetaxel for 3 of every 4 weeks plus daily ketoconazole. A variety of combination regimens was investigated. Weekly docetaxel doses ranged from 5 to 43 mg/m2, with starting doses of 600, 800 or 1,200 mg ketoconazole daily.

The resultsof this trial showed the following:

  • PSA levels were lowered by ≥ 50 percent in 26/42 patients (62 percent).
  • 7/25 patients (28 percent) with soft tissue disease had a partial response to therapy.
  • Median overall survival was 22.8 months and was significantly greater in docetaxel-naïve patients than in patients pretreated with docetaxel (36.8 vs 10.3 months, p = 0.0001).
  • The most frequently observed adverse events were anemia, edema, fatigue, diarrhea, nausea, sensory neuropathy, and elevated liver function tests.
  • There was a clear correlation between docetaxel clearance and ketoconazole exposure.
  • Concomitant ketoconazole increased docetaxel exposure 2.6-fold at a ketoconazole 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 authors conclude that combination regimens using 600 mg ketoconazole daily were fairly well tolerated and that the maximum tolerated dose of docetaxel on combination with ketoconazole was 32 mg/m2. They go on to suggest that this drug combination has significant antitumor activity in castration-resistant prostate cancer.

We are likely to see  some major changes to the recommended pattern of standard treatment for advanced prostate cancer over the next 3-5 years. Unanswered questions at this time include:

  • When is the most appropriate time to initiate immunotherapeutic treatment with sipuleucel-T?
  • Can and should sipuleucel-T be used to treat patients on multiple occasions?
  • When is the most appropriate time to initiate treatment with abiraterone acetate (assuming that this drug is proven to be effective and safe in ongoing Phase III clinical trials)?
  • Is the combination of docetaxel with ketoconazole more effective than ketoconazole alone in chemotherapy-naïve patients, implying that this may be the most appropriate form of first-line chemotherapy for patients who fail abiraterone (assuming that abiraterone should generally be given prior to chemotherapy)?

These are all questions that will need additional clinical data before we have good answers, and these questions apply only to drugs for which we already have relatively compelling data regarding their use or potential use in late stage disease. Other drugs that may well be vying for an appropriate place in the patient treatment paradigms — and that are already in or close to entering Phase III clinical trials — include atrasentan, ZD4054, MDV3100, TAK-700, dasatinib, ipilimumab, OGX-011, and a bunch of other, earlier-stage products. The good news is that there are going to be a lot of options for late-stage patients in the next few years, and many of those options will be accessible through clincial trials.

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