THE "NEW" PROSTATE CANCER INFOLINK

The evidence supporting a role for the combination of dutasteride with ketoconazole as a form of second- or third-line hormone therapy for patients with castration-resistant prostate cancer (CRPC) appears to be increasing.

On Tuesday this week, Taplin et al. published data from a Phase II trial of these two drugs in combination with hydrocortisone. The trial involved 57 patients with CRPC who were continued on gonadal suppression (an LHRH agonist or orchiectomy, we assume) and also treated with ketoconazole (400 mg three times daily), hydrocortisone (30 mg each morning, 10 mg each evening), and dutasteride (0.5 mg/day). The results of the study are reported to show that:

• 32/57 patients had a decline in their PSA of ≥ 50 percent.
• The median duration of response was 20 months.
• Of the 20 patients with measurable disease, 6 (30 percent) responded according to the Response Evaluation Criteria in Solid Tumors (RECIST).
• The median duration of treatment was 8 months.
• 9/57 patients remained on therapy with treatment durations censored at 18 to 32 months.
• Median time to disease progression was 14.5 months.
• Grade 3 toxicities occurred in 18/57 patients (32 percent) with only one reported grade 4 (thrombosis) toxicity.
• Dehydroepiandrosterone sulfate levels declined by 89 percent, androstenedione by 56 poercent, and testosterone by 66 percent
• Dihydrotestosterone declined to below detectable levels compared with baseline levels with testicular suppression alone.
• Median baseline levels and declines in dehydroepiandrosterone sulfate, androstenedione, testosterone, and dihydrotestosterone were not statistically different in the responders as compared to non-responders, and hormone levels were not significantly increased from nadir levels at relapse.

Taplin and her colleagues conclude that the response to this combination of ketoconazole, hydrocortisone, and dutasteride was at least comparable with responses to previous studies of ketoconazole alone, whereas time to progression was substantially longer.

There seems to be little doubt that the addition of dutasteride to ketoconazole has a meaningful clinical effect in at least some patients with CPRC. The questions that will now need to be answered are:

• Is this effect sufficient to “standardize” ketoconazole + dutasteride as a form of late-stage hormone therapy for carefully selected men failing standard forms of androgen deprivation therapy (ADT)?
• Are the adverse effects associated with ketoconazole therapy ufficiently manageable in the patients eligible for this form of treatment (because 1 32 percent occurrence of grade 3 toxicities is far from negligible)?
• Assuming that the newer CYP17A inhibitor, abiraterone acetate, demonstrates sufficient effectiveness and safety in Phase III trials to be approved for clinical use, will the addition of dutasteride to abiraterone acetate have similar (and possibly even more significant) clinical impact?

We seem to be entering a new era in which we will need to rethink the use of combinations of hormonally active agents in targeting multiple steps in androgen synthesis in order to optimize survival and quality of life for men with historically hormone-resistant forms of prostate cancer.

Filed under: Management, Treatment, Uncategorized Tagged: | castration-resistant prostate cancer, CRPC, dutasteride, ketoconazole