Spurred by evidence that androgens remain a key factor in the progression of hormone-refractory prostate cancer, novel approaches to hormonal manipulation have begun the transit from laboratory to clinical evaluation, and some of the preliminary results are encouraging.
Orlando, FL-Spurred by evidence that androgens remain a key factor in the progression of hormone-refractory prostate cancer, novel approaches to hormonal manipulation have begun the transit from laboratory to clinical evaluation, and some of the preliminary results are encouraging, a British oncologist reported at the Prostate Cancer Symposium here.
As an example of the more promising work, a phase I/II clinical trial of the androgen biosynthesis inhibitor abiraterone (CB7630) demonstrated dramatic PSA responses and evidence of tumor and lymph node shrinkage. The response has been maintained with follow-up exceeding 1 year in some patients.
"There are many hypotheses about the origin of androgen resistance, but their clinical relevance often remains unknown or uncertain," said Johann Sebastian de Bono, MB ChB, PhD, leader of the prostate cancer team at the Institute of Cancer Research and Royal Marsden Hospital in Sutton, U.K. "It is key that we run hypothesis-testing trials in the clinic to evaluate whether there are actually robust arguments for the management of our patients."
Evidence from multiple studies has shown that hormones or steroids upstream to the enzyme can activate the androgen receptor. Inhibition of the enzyme "ablates the generation of testosterone to dihydrotestosterone and the C17 steroids downstream of p450c17," Dr. de Bono said.
The phase I/II investigation from Royal Marsden involved patients who progressed despite treatment with multiple androgen-suppressing therapies. It began with a dose-finding study in which patients received abiraterone doses ranging between 250 and 2,000 mg per day. Two of the three patients who received the 250-mg starting dose remain on treatment after more than 1 year of follow-up.
Of the first 30 patients treated, 18 (60%) had PSA declines of 50% or greater, Dr. de Bono said. Assessment by Response Evaluation in Solid Tumors (RECIST) criteria showed that five of 10 evaluable patients had radiologic responses. Investigators have documented evidence of regression of bone disease, lymph node shrinkage, and objective responses in lung metastases. Responses have occurred at every dose level of abiraterone evaluated
Safety data on a total of 46 patients revealed grade 3 adverse events in two patients (one case each of nausea and fatigue). Otherwise, adverse events have been mild or moderate in severity, and no patient required a dose reduction because of adverse events. The most common adverse event has been hypokalemia (29 patients), which has been easily managed with supplemental potassium or eplerenone (Inspra), said Dr. de Bono. Other grade 1 or 2 adverse events included fatigue in 15 patients, hypertension in 10, and edema and anorexia in six patients each.
Promising results with abiraterone have continued to emerge in a phase II trial involving patients who had progressed on docetaxel (Taxotere) and other therapies. PSA declines of >50% occurred in eight of the first 13 patients treated, and two of these eight men had PSA declines of 90% or more. Patients also demonstrated improvement in symptoms and performance status and decreased need for analgesics.
Further, at press time, a total of 57 patients (38 who were chemotherapy-naïve and 19 were treated with docetaxel) have been treated with abiraterone. Of the 19 docetaxel patients, 10 progressed and nine dropped out of the study due to docetaxel-related toxicity. In this subset of patients, no difference in response to abiraterone was seen between those who progressed and those who discontinued docetaxel treatment.
"We now have evidence to suggest that a substantial proportion of what we call hormone-refractory prostate cancer remains hormone-driven prostate cancer," Dr. de Bono said, but he cautioned that more studies, particularly laboratory studies, are needed.
Results with other novel approaches to treating advanced prostate cancer patients have been mixed. Molecules targeting the erbB receptors have been disappointing, Dr. de Bono said. Antiangiogenesis drugs have produced some evidence of antitumor activity, but they have been infrequent. A recently completed phase I trial of an agent that inhibits poly (ADP-Ribose) polymerase yielded some promising evidence of activity in patients who have familial prostate cancer associated with BRCA2 mutations or BRCA loss of function. Other targeting strategies under investigation include survivin, which influences apoptosis and mitosis, and molecules that target insulin-like growth factor-1 receptor.