N4 Phase II study of ketoconazole combined with weekly doxorubicin in patients with hormone-refractory prostate cancer

Estramustine phosphate +/− vinblastine is and effective 1^st line salvage treatment for hormone-refractory prostate cancer (HRPC). Nevertheless, the prognosis subsequent to progression after 1^st line therapy is poor. We report the results with high doses of ketoconazole (KET) with hydrocortisone substitution and weekly doxorubicin (DOX). The principal end-point of the study was PSA response.

The study comprised 40 patients (pts) with HRPC managed with KET 400 mg TID with remplacement hydrocortisone (30 mg) per os DOX 35 mg/ sqm/ weekly, until progression. The pts were monitored clinically and with PSA measurement every 3 months (m). The pts with NR/PD are referred to chemotherapeutical regimens (docetaxel+pronisone).

The median age was 71.5 years (y)(range 45–79), ECOG performance status 1 (range 0–2). All pts had PSA progression, 36 (90%) had bone metastasis (painfull in 61% pts) and 16 (40%) had measurable soft tissue metastasis. All pts have undergone bilateral orchiectomy at 1^st line hormonal therapy. The median interval from diagnosis to the development of HRPC was 22.3 m (range 2.5–205.7). At beginning of therapy, the mean PSA value was 56.5 ng/ml (range 4.5–1580). The median number of courses administrated was 7.5 (range 2–17). The median cumulative dose of DOX was 225 mg/sqm (range 50–600). The dose of KET was reduced IN 14 pts (35%). With a median follow-up of 19.5 months (m), 9 pts (22%) were alive with no progression. In 31 pts (78%), their ds had progressed and they died of their ds. The median overall survival (OS) time was 13.05 m (95% CI, 8.7–17.3%) and the median time to progression was 3.9 m (95% CI, 2.0–5.9%). The overall PSA response was 45% 995% CI, 26–62%), 6 pts (15%) had no response and in 16 (40%), the ds progressed. Of 16 pts with measurable ds, the overall response rate was 375 9955 CI, 8–15%), with 2 complete (12%) and 4 partial (29%) response. 4 pts (25%) had no change and 6 (41%) their ds progressed. Using the PSA decline >50% the median survival time for responders was 24 m compared to 9 m for non-responders (p = 0.0089). Toxicity was mild, with only 4 cases of non-hematologic grade 3 or 4 toxicity. The most frequent toxicity was nail changes (12), wich was mainly grade 1 (8).

The combination of weekly DOX and KET is and effective, well-tolerated,2^nd line CT for HRPC acompained with mild toxicity. A PSA decrease >50% appears to represent significant marker in survival in group of pts with apparently refractory, but still hormone sensitive PC. PSA response to KET+DOX can be indentified within 1^st 6–8 weeks of therapy allowing an early indentification of responders and non-responders. Responders wll benefit from continuation of therapy and non-responders might be recruited for salvage cytotoxic regimens at an early stage