Abstract
74 Background: Recent data suggest that carboplatin may be effective in combination with docetaxel in DRPC. Platinum(II)-complexes have been shown to interfere with testosterone biosynthesis by inhibiting the cholesterol side chain cleavage enzyme (CYP11A1), 3b-hydroxysteroid dehydrogenase (HSD3B1,2) and 17a hydroxylase/C17,20-lyase (CYP17A1). Methods: Docetaxel failure/resistance was defined according to the Prostate Cancer Working Group (PCWG2 2007) criteria. Since February 2005, 68 consecutive DRPC pts were treated with at least two cycles of carboplatin AUC5 iv for 30 min on day 1 every 4 weeks (q4w), docetaxel at a dose of 35 mg/m2 iv for one hour on days 1, 8, (15) plus prednisone 2x5mg/day orally after receiving informed consent until disease progression or occurrence of intolerable adverse effects. Efficacy measures were done following PCWG2 recommendations. Free testosterone levels were measured before (n=42) and during DC treatment (n=36). Results: Response of prostate-specific antigen (PSAR; ≥50% PSA) was observed in 32/68 (47.1%) patients. At the time of the current analysis the median follow-up time was 13.6 months and 43/68 patients had died. Median progression-free survival (PFS) for all patients was 7.5 months (CI 95% 5.4, 9.5) and median overall survival (OS) was 18.6 months (CI 95% 12.3, 24.9). In PSAR, PFS was 15.7 versus 4.8 months in PSANR (p<0.001; hazard ratio HR 0.19, CI 0.09, 0.39) and OS was 25.6 versus 8.1 months (p<0.001; HR 0.21 CI 0.10, 0.42). This regimen was reasonably well tolerated, with leukopenia/neutropenia as the most common reversible grade 3/4 toxicity (39.7/33.8%). Median free testosterone levels were 0.935 pg/ml before and 0.185 pg/ml during DC treatment (nadir; p<0.001). While free testosterone levels before DC treatment were associated with lower PSAR (HR 6.32 CI 1.60, 25,0; p=0.009), free testosterone nadir levels <0.18 pg/ml during DC treatment were associated with higher PFS (HR 0.126 CI 0.04, 0.46, p=0.002) and OS (HR 0.07 CI 0.008, 0.53; p=0.01). Conclusions: These data suggest that DC may be an important second-line treatment option for DRPC patients by inhibiting the testosterone biosynthesis.
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