Abstract No.: 5017
Citation: J Clin Oncol 26: 2008 (May 20 suppl; abstr 5017)
Author(s):
C. J. Logothetis, S. Wen, A. Molina, N. Chieffo, L. A. Smith, P. Troncoso, E. Efstathiou
Background: Responses to the CYP 17 inhibitor, AA, confirm the therapeutic significance of persistent androgen signaling in CRPC. Elucidating the source of residual androgens and validation of predictive markers will lead to individualized androgen deprivation therapy in CRPC.
Methods: We performed an exploratory study to screen for associations between serum (endocrine) and microenvironment (paracrine) androgen concentration and response to AA. Study pts had bone metastases and a BM biopsy. Pts received oral AA 1,000mg QD and prednisone 10mg QD and had to have baseline <50ng/dl serum testosterone (S-T).
Results: Seventeen CRPC pts were enrolled. Median PSA concentration: 192.3 (range, 5.6-1971). Median age: 73 (range, 52-84), median performance status (PS-ECOG) 2 (range 0-2).Prior therapy: secondary hormonal treatment 13 (76%) ,chemotherapy 14(82.3%). No correlation between baseline S-T levels (median 28 ng/dl range <10-41) and bone marrow testosterone (BM-T) levels (median 13.17ng/dl, range <10-81) was noted (p value 0.28 Spearman's test). Eleven of 17 (58.8%) pts had a PSA decline and 7/17(41.1%) had a greater than 50% decline following 8 weeks of treatment. One pt has progressed. Improvement in PS occurred in 8/17 (47%). No > grade 3 treatment related toxicity occured. Two of 17 pts experienced grade 1 hypokalemia and hypertension respectively. Decline below detectable levels (<10ng/ml) in S-T occurred in all study pts (17/17) and in BM-T in 9/9 evaluable pts. Higher baseline BM- T correlated with >50 % PSA decline (p value: 0.05 t test, p value: 0.06 Wilcoxon test,). Median Baseline BM-T of these pts was 24.45 (range <10-81ng/dl). Heterogeneous CYP17 expression was observed in all BM metastatic lesions. (20-100% tumor involvement).
Conclusions:
CYP17 blockade results in PSA decline in select pts with advanced CRPC without significant toxicity. The observed correlation between baseline BM -T level and PSA decline suggest that BM-T may serve as a predictive marker. CYP 17 expression in bone metastases suggests that CYP17 is an adaptive response to castration Significance: The ongoing study of androgen signaling in CRPC may lead to markers that will predict for PSA decline with CYP 17 inhibition.