Health and Prostate

Each year in the United States, 317,000 cases of prostate cancer are reported, with 41,400 men dying from it. About 50% of patients suffer from metastatic disease when they are diagnosed. These patients are treated with medical or surgical castration that may or may not involve antiandrogens. This first-line therapy has no effect on progression for 20% to 30% of patients. The remaining 70% to 80% experience relapse within the next three years and may qualify for second-line therapy options, which include cyproterone acetate, a synthetic antiandrogen steroid, and liarozole, the first retinoic acid metabolism-blocking agent.

Liarozole, a novel imidazole derivative, is the first retinoic acid metabolism-blocking agent (RAMBA) to be developed as differentiation therapy for human solid tumors. Most importantly, the drug has been shown to demonstrate anticarcinogenic and antitumor effects. Preclinical studies of liarozole have shown that it inhibits the growth of androgen-independent tumors, along with others, by inhibiting 4-hydroxylase, a cytochrome P450-dependent enzyme that is involved in retinoic acid catabolism. A recent study compared the ability of these two drugs to induce prostate-specific antigen (PSA) response in patients with metastatic prostate cancer that is progressing in response to first-line endocrine therapy. The multicenter, randomized trial consisted of 321 patients who had been recruited from 53 centers in 10 countries. Median age at the beginning of the trial was 72 years, with a range of 46 to 88 years. All patients except one were white. Identified as prognostic factors for survival were baseline hemoglobin, alkaline phosphatase, PSA, duration of response to first-line treatment, and performance status. Because most patients with prostate cancer do not present assessable lesions, it is difficult to evaluate objective tumor response. As a result, prostate-specific antigen (PSA) was used in this study as a marker for tumor response.

Liarozole was started at 150 mg twice daily and then increased 300 mg twice daily for the remainder of the treatment. The cyproterone acetate (CPA) dose used was 100 mg twice daily from the start of the study and remained the same unless dosage adjustments were necessary according to prescribing information. Treatment continued until clinical progression was shown or a serious adverse event occurred. Patients were followed up until death. The trial was analyzed after 232 deaths.

Prostate-specific antigen (PSA) responders were more prevalent in the liarozole group (20%) than in the cyproterone acetate group (4%), p < 0.001. PSA stabilization occurred in 64% of patients in the liarozole group. Changes indicative of continuous progression were observed in 17% of patients treated with liarozole, in contrast to 40% of patients in the cyproterone acetate group. The response was not affected by previous use of antiandrogens in either treatment group.

Prostate-specific antigen (PSA) response occurred by week 12 in 90% of responding patients. The median time to progression was 4.6 months in the liarozole group and 3.6 months in the cyproterone group. Patients who had a PSA response experienced a median survival of 25 months. Those who experienced stabilization survived for 14 months, and patients with continuous progression survived for 7 months. PSA responders had a 57% lower risk of dying as compared with nonresponders.

When comparing the two drugs, after adjustment for baseline prognostic factors, the study showed that patients treated with liarozole survived longer and had a 26% lower risk of dying than did patients on cyproterone acetate. Liarozole treatment resulted in a significantly better PSA response (20% of patients compared with 4% of the cyproterone group). Also, PSA stabilization was observed in 64% of the liarozole group. Participants in both groups of the trial reported various adverse events. In the liarozole group, the most common problems were dry skin, pruritus, rash, nail disorders, and hair loss. Patients undergoing cyproterone acetate treatment suffered from edema, nausea, vomiting, and fatigue. For the most part, these conditions were mild to moderate. Adverse events caused withdrawal from treatment for 88 patients in the liarozole group and 63 patients in the cyproterone acetate group. Most of the withdrawals occurred because of cancer-related events such as skin disorders, nausea, and vomiting.

Patients with metastatic prostate cancer usually complain of bone pain due to skeletal involvement. Advanced prostate cancer patients will also present with signs and symptoms of lymphadenopathy, lower extremity edema, renal failure, visceral metastases, anemia and cachexia. Prostate cancer and these accompanying medical conditions can lead to a lot of pain and poor performance status.

In conclusion, this trial shows that prostate-specific antigen (PSA) response is an effective way to measure the clinical benefits of prostate cancer therapies. Patients who experienced this response lived longer, had less pain, and an improvement in quality of life. Liarozole was shown to be more effective than cyproterone acetate in achieving PSA response and in treating relapsed prostate cancer.