LIAROZOLE - A NOVEL TREATMENT APPROACH FOR ADVANCED PROSTATE-CANCER -RESULTS OF A LARGE RANDOMIZED TRIAL VERSUS CYPROTERONE-ACETATE

Objectives. To compare the efficacy of oral liarozole, the first retin oic acid metabolism-blocking agent (RAMBA) to be developed as differen tiation therapy for human solid tumors, with that of cyproterone aceta te (CPA), an antiandrogen for the treatment of metastatic prostate can cer. Liarozole promotes differentiation of cancer cells by increasing the intratumoral levels of retinoic acid. Methods. A total of 321 pati ents with metastatic prostate cancer in relapse after first-line endoc rine therapy entered a Phase III international multicenter study (recr uitment from February 1992 to August 1994) comparing liarozole (300 mg two times daily) with CPA (100 mg two times daily). Results. Accounti ng for differences in baseline prognostic factors, the adjusted hazard ratio for survival was 0.74 in favor of liarozole (P = 0.039), indica ting a 26% lower risk of death than in patients treated with CPA. Medi an crude (unadjusted) survival time was the same in the liarozole grou p as in the CPA group (10.3 months). More patients showed a PSA respon se (at least 50% reduction in PSA from baseline) when treated with lia rozole (20%) than with CPA (4%) (P < 0.001). Prostate-specific antigen (PSA) responders had a median survival benefit of 10 months over nonr esponders, irrespective of treatment (hazard ratio 0.43; P = 0.0018). PSA response was apparent within 3 months in approximately 90% of pati ents who responded. Pain improved more in the liarozole group than in the CPA group (P = 0.03). PSA responders had lower median pain scores than nonresponders (1.7 versus 2.5) and better quality of life (median Functional Living Index-Cancer score 108 versus 98) at end point, ie, treatment discontinuation, as well as throughout the treatment period . Among the most frequently occurring adverse events in the liarozole group were dry skin (51% of patients), pruritus (25%), rash (16%), nai l disorders (16%), and hair loss (15%). These adverse events were gene rally mild to moderate in severity and did not affect the overall qual ity of life score. There were no detectable effects of either treatmen t on vital signs such as blood pressure, heart rate, electrocardiogram , and body weight. Conclusions. Liarozole is superior to CPA in terms of PSA response, PSA progression, and survival, and is capable of main taining patients' quality of life. The observed adverse events were mi ld to moderate in nature. These results show that liarozole is a possi ble treatment option after first-line endocrine therapy has failed. (C ) 1998, Elsevier Science Inc. All rights reserved.