BERKELEY, CA (UroToday.com) - Despite a recorded decrease of prostate cancer-related deaths recorded from 1990 to date, the diagnosis of this disease still remains the most common among men in the US.
Hormone therapy is able to induce tumor growth control in more than 90% of patients independently of the different treatment modalities but notwithstanding these results, all tumors eventually progress after becoming resistant to castration (CRPC).
The study, Tax 327, showed the ability of docetaxel as compared to mitoxantrone to significantly extend the overall survival of patients affected by CRPC. There is now unquestionable evidence that CRPC remains hormone driven because of the intra-tumor steroid synthesis that fosters tumor growth. In this scenario the inhibition of steroidogenesis at adrenal level represents one of the possible anti-tumor mechanisms to target in clinical trials. Ketoconazole inhibits the cytochrome P450 14-α-demethylase (P45014DM), the C-17, 20-lyase and the C-17-α-hydroxylase, and consequently the adrenal androgen synthesis. Clinical studies have shown a moderate anti-tumour efficacy of ketoconazole employed at different dose levels after the failure of androgen suppressive therapies.
This phase II study reports a mono institutional experience on the use of continuous low- dose ketoconazole in patients with CRPC who received (or not) docetaxel as first-line chemotherapy. The primary endpoint was the rate of biochemical responses - whereas objective responses, progression-free survival, and safety were the secondary endpoints.
Thirty-seven patients with CRPC were enrolled: 15 had been previously treated with docetaxel and 30 received ≥2 lines of hormonal treatments. Their median age was 75 years (range 60–88), 84% had metastatic disease. Among the whole population, two patients reported a complete biochemical response and six patients a partial biochemical response; overall disease control rate (CR+PR+SD) was recorded in 56% of cases while the clinical benefit (CR+PR+SD > 6 months) was observed in 29%. The sub-group analysis of patients previously treated with docetaxel showed a disease control rate and a clinical benefit in 46% and 33% of patients, respectively. The median duration of treatment was 21 weeks and the median progression-free survival 21.5 weeks. Treatment was well tolerated: grade 3/4 toxicities were not reported and the most common adverse events were asthenia followed by vomiting, fatigue and abdominal pain.
Docetaxel-based chemotherapy changed the therapeutic approach to symptomatic or asymptomatic patients with extensive CRPC: nevertheless docetaxel is not always feasible on account of age and comorbidities. Until recently, no agent was effective in improving the course of docetaxel-resistant disease.
Recent studies have shown the ability of abiraterone acetate, a selective inhibitor of 17-α-hydroxylase/17, 20-lyase (CYP 17), to reduce the extra-gonadic production of testosterone and also the disease progression for CRPC. Additionally a new agent, cabazitaxel, demonstrated in a phase 3 trial an improvement of OS when compared to mitoxantrone after first-line docetaxel.
Although the small sample size doesn’t allow further comments, our study confirms that the synthesis of testosterone has a role in patients pretreated with docetaxel. The key messages are: low-dose ketoconazole is safe and feasible; the anti-tumor activity was confirmed in patients refractory to androgen suppressive treatment and to chemotherapy; the increase of ketoconazole dosage could be associated with a better outcome. An additional randomized study has been designed in CRPC to assess the ketoconazole clinical activity and the improvement of quality of life.
R.Iacovelli,1 I.Testa,2 and G.Procopio2 as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
- Department of Radiology, Oncology and Human Pathology, “Sapienza” University of Rome, Rome, Italy.
- Department of Medical Oncology, Istituto Nazionale dei Tumori of Milan, Milan, Italy.