February 18, 2007. — A new anti-cancer drug that blocks the human epidermal growth factor (HER) receptor family "shows promise" in prolonging the lives of patients with recurrent prostate cancer, according to Dr. David Agus, a researcher involved in a study reported in the Journal of Clinical Oncology this week.
The same monoclonal antibody failed to impress investigators who conducted a similar clinical trial in the UK. The USA study found that although no substantial PSA drops or tumor shrinkage occurred, some patients who received the drug appear to have gained several months of life.
Pertuzumab (rhuMAb 2C4) belongs to a new class of targeted drugs called human epidermal growth factor receptor (HER) dimerization inhibitors. It works by binding to and inhibiting the function of HER2 receptors. The aim is to block a key pathway that leads to cancer growth.
The USA study, a phase II clinical trial, was designed to assess the safety and efficacy of pertuzumab given without other therapy to patients whose prostate cancer no longer responded to androgen blockade and had progressed after prior chemotherapy.
The study enrolled 42 patients of whom one dropped out before any assessment could be made. The remaining 41 patients received pertuzumab every 3 weeks. All of the patients were at a stage at which their prostate cancer was advancing despite testosterone suppression. All had experienced progression after at least one taxane-based regimen.
All patients received a loading dose of 840 mg pertuzumab (cycle 1) followed by 420 mg for subsequent cycles. The main aims of the trial were to test overall response of the disease to the drug and the drug's safety. A separate retrospective analysis of actual survival time versus predicted survival time for a patient population with comparable prognostic features was performed.
Patients continued to receive the drug every three weeks until disease progression. MRI and CAT scans were used to evaluate the tumors during the period of drug therapy. All of the patients were able to tolerate the drug, although sixty percent percent developed diarrhea.
The results look disappointing considering that no patients had complete or partial responses. None showed tumor shrinkage. And none showed 50% or greater decline in PSA.
At the same time, a finding of extended survival time following failure of Taxotere was calculated on the basis of the fact that a handful of this group of "heavily pretreated" men experienced many weeks of stable disease.
Of 30 "efficacy-assessable patients," five had stable disease (SD) for at least 23 weeks; one of the five had stable disease for 36 weeks
Retrospective analysis showed, the study authors say, that survival rate was prolonged to a median of 16.4 months with the drug as compared to a median average of 10.7 months in a historical control group with similar baseline prognostic features.
"Advanced prostate cancer is difficult to treat -- and the drug therapies currently available to these patients have not been very effective, especially in patients whose disease has progressed after chemotherapy treatment," said David B. Agus, M.D., principal investigator of the study and research director of Cedars-Sinai's Louis Warschaw Prostate Cancer Center at the Samuel Oschin Comprehensive Cancer Institute. "Pertuzumab may offer a new treatment approach for these patients when it is evaluated as a tool to slow -- not stop or shrink -- tumor growth."
"The theory is that by significantly slowing progression of the cancer, patients will experience a good quality of life for a longer period of time," said Agus. "Ultimately, we hope drugs like pertuzumab will help us reach the point where cancer can be viewed as a lifetime disease to be managed much like AIDS is looked at now. This would be major shift from the current paradigm for cancer treatment, and is a promising area of research. This study must be viewed cautiously, however, as we are comparing statistics from historical control groups."
According to the researchers, this study of pertuzumab raises the question, which clinical outcome standards or end points are appropriate for studies involving patients with advanced prostate cancer -- patients who have limited options.
Previous research published by cancer researchers at Cedars-Sinai and other institutions has shown that pertuzumab affects the growth of several other types of cancers, including breast, ovarian and lung cancer, and that the drug may also prolong survival for patients with advanced ovarian cancer.
The next step is to test pertuzumab on a larger group of patients in a randomized fashion, and to analyze data that is not retrospective.
The study is published in Journal of Clinical Oncology , Vol 25, No 6 (February 20), 2007: pp. 675-681. Efficacy and Safety of Single-Agent Pertuzumab (rhuMAb 2C4), a Human Epidermal Growth Factor Receptor Dimerization Inhibitor, in Castration-Resistant Prostate Cancer After Progression From Taxane-Based Therapy
David B. Agus , Christopher J. Sweeney , Michael J. Morris , David S. Mendelson, Douglas G. McNeel , Frederick R. Ahmann , Jin Wang , Mika K. Derynck , Kimmie Ng , Benjamin Lyons , David E. Allison , Michael W. Kattan , Howard I. Scher.
From the Cedars-Sinai Prostate Cancer Center, Los Angeles; Genentech Inc, South San Francisco, CA; Indiana University Medical Center, Indianapolis, IN; Memorial Sloan-Kettering Cancer Center, New York, NY; Premiere Oncology of Arizona, Scottsdale; Arizona Cancer Center, Tucson, AZ; University of Wisconsin, Madison, WI; and the Cleveland Clinic Foundation, Cleveland, OH
The research was supported by Genentech, Inc. and the National Cancer Institute Specialized Program of Research Excellence (SPORE) program.
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