Recent data suggest that carboplatin plus weekly docetaxel (DC) may be effective in mDRPC. Platinum(II)-complexes have been shown to interfere with steroid biosynthesis lowering testosterone levels by inhibiting the cholesterol side chain cleavage enzyme (CYP11A1), 3β-hydroxysteroid dehydrogenase (HSD3B1,2) and 17α hydroxylase/C17,20-lyase (CYP17A1).
Docetaxel failure/resistance was defined according to the Prostate Cancer Working Group (PCWG2 2007) criteria. Treatment consisted of 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 = 82) and during carboplatin/docetaxel chemotherapy (n = 76).
Of the 106 pts. treated since February 2005, 96.2% had bone and 63.2 % soft tissue metastases ( 45% lymph node, 27% liver and 21% lung involvement). At the time of the current analysis, the median follow-up time was 13.5 months, 101 pts. had died and 102 had progressive disease. The objective response rate was 43.2% and the disease control rate 64.2% in the 67 pts. with measureable disease. Response of prostate-specific antigen (≥50%) was observed in 50 patients (47.1%). Median progression-free survival (PFS) for all patients was 6.9 months (CI 95% 5.7, 8.0) and median OS was 14.1 months (CI 95% 10.9, 17.3). The most common reversible grade 3/4 toxicity was leukopenia/ neutropenia (40.5/32.1%). Median free and total testosterone levels were reduced below the detection limit during DC treatment (from 0.55 pg/ml to < 0.18 pg/ml and 0.08 to < 0.05 ng/ml, respectively). Testosterone nadir values <0.18 pg/ml during DC treatment were associated with longer PFS, OS and post-hoc OS (p < 0.05).
These data suggest that carboplatin plus weekly docetaxel may be an important second-line treatment option for DRPC patients by inhibition the testosterone biosynthesis.
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C.W.M. Reuter: Advisory board: Eisai, Bayer, Tesaro, Sanofi, Astellas, Janssen. All other authors have declared no conflicts of interest.