Salvage chemotherapy with carboplatin plus weekly docetaxel in patients (pts) with castration- and docetaxel-resistant prostate cancer (DRPC): Associations of patient and disease characteristics with overall survival (OS).

75 Background: Our recent data suggest that carboplatin is effective in combination with docetaxel (DC) in docetaxel-resistant prostate cancer (DRPC). Platinum(II)-complexes 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). Methods: 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 one every 4 weeks (q4w), docetaxel 35 mg/m2 iv for one hour on days 1, 8, and 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=59) and during DC chemotherapy (n=52). Results: Of the 82 pts treated since February 2005, 95.1% had bone, 42.7% had lymph node, 26.8% liver, and 18.3% lung involvement. At the current analysis, the median follow-up time was 15.6 months. The objective response rate was 40.8% and the disease control rate 63.3% in the 49 pts with measureable disease. Response of prostate-specific antigen (greater than or equal to 50%) was observed in 3 out of /82 (47.6%) pts. Median progression-free survival (PFS) was 6.9 months (CI 95% 6.0, 7.8) and median OS was 18.0 months (CI 95% 12.7, 23.3). The most common reversible grade 3/4 toxicity was leukopenia/neutropenia (42.7/37.8%). Median free testosterone (fT) was 0.745 pg/ml before and less than 0.18 pg/ml during DC treatment (nadir levels, p=0.009; detection limit less than 0.18 pg/ml) and median serum androgene (T+DHT=TA) was 0.19 ng/ml and below the detection limit of less than 0.05 ng/ml (p<0.001). In multivariate analyses, lactate dehydrogenase, PSA response, and fT and TA nadir levels were associated with longer OS (p<0.05). Conclusions: These data suggest that carboplatin plus weekly docetaxel may be an important second-line treatment option for DRPC patients by inhibiting the testosterone biosynthesis.