Anti-tumor activity of abiraterone acetate (AA), a CYP17 inhibitor of androgen synthesis, in chemotherapy naive and docetaxel pre-treated castration resistant prostate cancer (CRPC)

Abstract

5005 Background: AA is an oral irreversible inhibitor of CYP17 (17α-hydroxylase/ C17,20-lyase) and of androgen synthesis under evaluation for the treatment of CRPC pts. Methods: Since 2005 CRPC pts who have failed androgen deprivation therapy (ADT) have been enrolled into two parallel trials of AA: i) Phase I/II study in chemo-naïve CRPC and ii) Phase II study in CRPC post-docetaxel. Both Phase II trials utilized a two-stage Simon design with Ho of 10% and Ha of 30%, α = 0.05; β = 0.1 and PSA response (≥50% decline) by PSAWG criteria as the primary endpoint for response evaluation. Results: 86 pts were treated and 72 are evaluable for response. In the 1st study AA was well tolerated at all dose levels (250–2000 mg) with no DLT; 1000 mg was the selected Phase II dose based on PK-PD evaluation. Both Phase II trials have rejected the null hypothesis with the ≥50% PSA response exceeding 60% in the chemo-naïve cohort and exceeding 40% in the taxane treated cohort. Chemo-naïve pts (n=44) received a median of 3 prior hormonal treatments, with bone metastases in 70% of pts and measurable disease by RECIST in 21 pts; 12/21 pts had a PR by RECIST. Median time to PSA progression (TTPP) was 252 days. 14 pts on AA received >12 cycles (48 weeks). In post-docetaxel pts (n=28), > 80% had bone metastases and 18/28 were evaulable by RECIST, with 4 achieving PR; 11 pts remain on study >6 months and 5 pts > 12 cycles. Median TTPP is 167 days. Improved symptoms, decreased analgesic requirement and falls in circulating tumor cell counts have been observed. Mechanism-based AEs secondary to mineralocorticoid excess consisting primarily of Grade 1–2 hypertension, hypokalemia and fluid retention were reversible with concomitant eplerenone or low-dose corticosteroids. Using an ultra-sensitive serum testosterone (T) assay, significant T suppression, beyond that achieved by conventional ADT was detected. Conclusions: AA is well tolerated and produces encouraging anti-tumor activity in CRPC. These results support emerging data indicating that CRPC frequently remains hormone driven despite progression following ADT and docetaxel-based chemotherapy. Randomized Phase III trials of AA will soon be initiated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Cougar Biotechnology Cougar Biotechnology