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CASTRATION-RESISTANT PROSTATE CANCER (CRPC): COMBINATION THERAPY OF ETHINYLESTRADIOL AND ESTRAMUSTINE PHOSPHATE REINTRODUCES OBJECTIVE CLINICAL RESPONSES. E. De Berardinis, G.M. Busetto, S. Salciccia, F. Di Silverio and V. Gentile. Sapienza Rome University Policlinico Umberto I. Scopo del lavoro Therapy for castrate-resistant prostate cancer (CRPC) centers on suppressing systemic androgens and blocking activation of the androgen receptor (AR). Despite anorchid serum androgen levels, nearly all patients develop castration-resistant disease. At this stage of the disease treatment is generally based on chemotherapy. In our research we wanted to evaluate whether a combination therapy of ethinylestradiol and estramustine phosphate was able to reintroduce an objective clinical response in these patients with refractory prostate cancer. Materiali e Metodi 31 patients (11 pts. Gleason score 8 (4+4), 13 pts. Gleason score 9 (5+4), 5 pts. Gleason score 10 (5+5)) with stage D3 disease and bone metastases who had progression despite initial responses to combined androgen blockade and in whom antiandrogen withdrawal subsequently failed discontinued combined androgen blockade and received 2 mg ethinylestradiol orally daily and oral estramustine 420 mg/daily. Serum prostate specific antigen (PSA), Eastern Cooperative Oncology Group performance status and bone pain scores were assessed at regular intervals. Median followup was 17 months (range 8 to 26). Risultati All cases (90%, 95% CI 55.5 to 99.8) had an objective clinical response, defined as a greater than 50% PSA decrease (median 87.1%, range 50.2% to 94.4%). PSA normalization (less than 4 ng/ml) was achieved in 3 cases. All patients reported significant and durable improvement in bone pain (median duration 17.5 months) and performance status (median duration 18 months). The most important side effects were: vein thrombosis (8 pz) and gastric pain (5 pz). Discussione Recent studies have shown that prostatic carcinoma cell becomes sensitive to low levels of androgens and that they themselves are produced by prostate cancer cells, or derived from the adrenal. Next to this interesting basic research, there is confirmation that prostate cell has an increased number of beta estrogen receptors (quantity) in addition to their overexpression (quality). Conclusion Is by now proven that CRPC is sensitive to androgens and prostate cancer could become hypersensitive to androgens low levels and is finally established that this cancer produces androgens by itself. We could improve our results in term of DFS and related therapy side-effects substituting Estracyt with new antiandrogen maintaining ethinylestradiol that acts on beta-oestrogenic receptors. References 1) Di Silverio F, Gagliardi V, Sorcini G, Sciarra F. Biosynthesis and methabolism of androgenic hormones in cancer of the prostate. Invest Urol 1976;13(4):286-8. 2) Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 2008;68:4447–54. 3) Yap TA, Carden CP, Attard G, de Bono JS. Targeting CYP17: established and novel approaches in prostate cancer. Curr Opin Pharmacol 2008;8:449–57. 4) Tindall DJ, Rittmaster RS. The rationale for inhibiting 5α-reductase isoenzymes in the prevention and treatment of prostate cancer. J Urol 2008;179:1235–42.