Zytiga Superior to Ketoconazole

Zytiga and Ketoconazole are both widely used in prostate cancer therapy and have a common mechanism of action both working by inhibiting the enzyme CYP17 which is responsible for androgen biosynthesis. Inhibiting this enzyme lowers testosterone levels which results in tumour regression. Ketoconazole is a non selective CYP inhibitor developed as an antifungal agent but was also found to inhibit a number of human CYP enzymes including CYP3A4 in the liver and CYP17 in the adrenals and testes. Zytiga is a specially designed inhibitor of CYP17 targetted specifically at this enzyme and is 10,000 times more potent as a CYP17 inhibitor than Ketoconazole.

The two drug have now been compared directly in clinical practice and as expected Zytiga showed superior overall survival results compared with Ketoconazole.

Comparison of Abiraterone Acetate (Zytiga) versus Ketoconazole in patients with metastatic castration-resistant prostate cancer (mCRPC) refractory to Docetaxel.

Background: Zytiga is standard treatment in patients with mCRPC refractory to docetaxel. Zytiga is a potent and selective CYP 17 inhibitor that blocks the synthesis of androgens in the testis, adrenal glands, and prostate tumour cells. However, in some countries where Zytiga has not been approved yet, Ketoconazole is used as an alternative CYP 17 inhibitor. Although preclinical data suggests that Ketoconazole is much less specific and potent as an inhibitor of CYP 17, there is no clinical data comparing both agents. The present study aimed to compare the clinical effectiveness of Zytiga vs Ketoconazole in patients with mCRPC refractory to Docetaxel.

Methods: Records from 156 mCRPC patients treated with Ketoconazole 200 - 400 mg 3x day, in 4 centers across the US were reviewed retrospectively. 26 pts treated post Docetaxel were individually matched by clinicopathologic factors to patients treated with Zytiga. We compared the PSA response (decrease ≥50% from baseline), biochemical (bPFS) and radiological (rPFS) progression free survival, and overall survival (OS) between the groups. Progression free survival and overall survival were determined by Cox regression.

Results: The groups were matched by Gleason score and disease extent (limited-axial skeleton and/or nodal vs extensive- appendicular skeleton and/or visceral). Furthermore, they were balanced regarding median age, PSA response and time to progression on prior Docetaxel.
In the groups of Zytiga vs Ketoconazole,

PSA response was 46% for Zytiga vs 19% for Ketoconazole,

Median biochemical bPFS 7 months for Zytiga vs 2 months for Ketoconazole,

Median radiological rPFS 6 months for Zytiga vs 2.5 months for Ketoconazole,

Median overall survival (OS) 17 months for Zytiga vs 12 months for Ketoconazole

Therefore treatment with Zytiga increases overal survival by an extra 5 months compared to treatment with Ketoconazole.

Conclusions: In mCRPC refractory to Docetaxel chemotherapy, the outcome of patients treated with Zytiga was superior to Ketoconazole.