Impact of prior ketoconazole therapy on response proportion to abiraterone acetate, a 17-alpha hydroxylase C17,20-lyase inhibitor in castration resistant prostate cancer (CRPC)

Steroidogenesis inhibitors alter but do not eliminate androgen synthesis mechanisms during progression to castration-resistance in LNCaP prostate xenografts

“…Interestingly CRPC patients who developed resistance following initial response to abiraterone acetate treatment did not have increased levels of CYP17A1 mediated steroid production in their serum as previously observed in the ketoconazole relapsing patients [48]. Furthermore in a Phase I clinical trial reported by Ryan et al 52% of patients (total 19) who previously became resistant to ketoconazole treatment displayed further PSA response (>50% decline) to abiraterone acetate treatment despite the fact that both drugs target the same enzyme [61]. Abiraterone acetate is a 20 times more potent inhibitor of CYP17A1 than ketoconazole [55] which is a broad spectrum inhibitor of steroid drug metabolism and this may explain why ketoconazole resistance can occur through alternative synthesis mechanisms while abiraterone acetate may completely block all androgen synthesis pathways downstream of CYP17A1.…”

Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target

“…The most recent data from treatment of >100 chemotherapy-naïve patients and >100 post-chemotherapy patients, reported at the 2009 ASCO Genitourinary Cancers Conference, showed significant efficacy with PSA declines of 50% or more in chemotherapy-naïve and ~40% in post-chemotherapy patients. The medium time to progression in these two patient groups was 8 and 5.5 months, respectively (48, 61, 62). This data has led to an ongoing multinational phase III trial of abiraterone vs placebo with a primary endpoint of overall survival, randomized in a 2:1 manner and targeted to accrue almost 1200 patients whose disease has progressed after docetaxel-based chemotherapy.…”

Alternative Strategies for the Treatment of Classical Congenital Adrenal Hyperplasia: Pitfalls and Promises

“…Abiraterone acetate is approximately six to seven times more potent in inhibiting CYP450c17 than ketoconazole [53]. Preclinical and phase I studies in patients with prostate cancer showed that abiraterone effectively suppresses testosterone production in the adrenal gland, and doses of up to 2000 mg/d were tolerated [54].…”