New Hormonal Treatment May Help in Castration-Resistant Prostate Cancer
Last Updated: 2010-04-14 19:30:39 -0400 (Reuters Health)
NEW YORK (Reuters Health) - A new high-affinity androgen-receptor antagonist was safe and tolerable for men with castration-resistant prostate cancer, according to dose-escalation study results -- and it showed promising antitumor effects as well.
The findings were reported online April 15th in The Lancet by Dr. Howard I. Scher, of the Memorial Sloan-Kettering Cancer Center in New York, and colleagues.
"Now is an exciting time to revisit targeted treatments in castration-resistant prostate cancer," Drs. William L. Dahut and Ravi A. Madan of the National Cancer Institute in Bethesda, Maryland, wrote in a comment.
"The last androgen-receptor antagonist was developed more than two decades ago; the prevailing philosophy since has been that sequential hormonal treatments are futile," they noted.
The new study tested MDV3100 -- an androgen-receptor antagonist developed by California-based Medivation -- in 140 patients with progressive, metastatic castration-resistant prostate cancer. In contrast to older androgen-receptor antagonists, MDV3100 has a high binding affinity without any agonist properties.
The men in the study had metastases in bone (75%), lymph nodes (54%), and viscera (9%). Their median age was 68 years.
The researchers tested seven different daily doses of MDV3100, ranging from 30 to 600 mg. The 25 patients in the 480- and 600-mg cohorts had already progressed on chemotherapy.
In total, 98 men discontinued treatment, due to radiologic progression (47), prostate cancer antigen (PSA) progression (17), clinical progression (16), adverse events (8), other reasons (7), or withdrawal of informed consent (3).
The median time on the drug was 21 weeks.
The most common grade 3 or 4 adverse event (using National Cancer Institute common terminology criteria for adverse events) was fatigue. This event occurred in 16 patients, but only at higher doses, and it disappeared with dose reduction. Three seizures occurred, although two of the patients had complicated medical histories.
Overall, 75 patients had received chemotherapy and 65 had not. The researchers found anti-tumor effects in both groups of patients and at all doses. The frequency of maximal PSA decreases of more than 50% did not differ significantly between the groups (62% vs 36 %, respectively).
The decline in PSA was dose-dependent up to 150 mg/day, with no additional benefit at higher doses.
Using the Prostate Cancer Clinical Trials Working Group 2 criteria of a 25% or greater increase in PSA from the nadir, the median time to PSA progression was 41 weeks for patients who hadn't received chemotherapy and 21 weeks for those who had.
Tumor regression -- "notoriously difficult to achieve in prostate cancer," according to Drs. Dahut and Madan -- was found in 13 of 59 patients with soft-tissue disease, while another 29 had stable disease. Sixty-one of 109 patients with bone involvement had stable disease.
Dr. Scher and his colleagues note that their findings support preclinical studies showing that androgen-receptor signaling may still drive prostate cancer in castration-resistant disease and highlight the potential clinical benefit of further endocrine treatment in such cases.
"MDV3100 could have the potential to significantly change treatment options in metastatic disease, even in the post-chemotherapy setting in which hormonal manipulations might have more use than was previously thought," the researchers conclude.
Drs. Dahut and Madan note that MDV3100 and abiraterone -- a modern inhibitor of androgen synthesis -- are both currently being tested in phase 3 studies.
The researchers have received funding from Medivation.
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