Abstract No.: 5005
Citation: J Clin Oncol 26: 2008 (May 20 suppl; abstr 5005)
Author(s):
J. S. De Bono, G. Attard, A. H. Reid, C. Parker, M. Dowsett, R. Mollife, T. A. Yap, A. Molina, G. Lee, D. Dearnaley
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.