An investigational drug that’s shown promise in men with advanced prostate cancer will now move one step further in clinical development. In Phase II clinical trials, MDV3100 has been shown to effectively lower prostate specific antigen (PSA) levels — a marker for tumor growth — in men with advanced prostate cancer who have no other treatment options. The investigational drug also has been shown to shrink prostate cancer lesions identified on imaging studies in some patients. Now, MDV3100 is moving forward to a Phase III clinical trial that will determine whether the drug extends the lives of men with advanced metastatic prostate cancer.
The Oregon Health & Science University Knight Cancer Institute is one of just three original centers worldwide to enroll participants in all phases of MDV3100 clinical trials. Two additional centers joined the study as it progressed. Recent findings from the phase I and II trials on MDV3100 are published in this week’s edition of The Lancet.
“This clinical trial is yet another example of how the OHSU Knight Cancer Institute is consistently able to bring the most exciting and promising new drugs and treatment options to Oregonians,” said Tomasz Beer, M.D., OHSU principal investigator, director of the Prostate Cancer Research Program, and deputy director of the OHSU Knight Cancer Institute. “We saw the majority of men respond favorably to treatment, including men whose cancers were resistant to both hormonal therapy and chemotherapy and who have no good treatment options today.”
Current treatments for men with metastatic prostate cancers, cancers that have spread beyond the original site, inhibit the activity of male hormones that help drive tumor growth. Many of these drugs disrupt the androgen (male hormone) receptor, which helps regulate cell proliferation. But tumors eventually become drug-resistant by expressing higher levels of the androgen receptor or by finding other means of circumventing current hormonal treatments. This overexpression of the androgen receptor contributes to the development of a more aggressive form of the illness called castration-resistant prostate cancer, or CRPC.
Armed with this knowledge, Charles Sawyers, M.D., chairman of human oncology and pathogenesis at Memorial Sloan-Kettering Cancer Center (MSKCC), and chemist Michael Jung, Ph.D., at UCLA, collaborated to review a number of compounds to determine which compounds could most effectively block the androgen receptor.
Two of the compounds evaluated, MDV3100 and RD162, were found to work well in cells in culture, shrink tumors in mouse models of prostate cancer, maintain tumor shrinkage for months, and prevent the androgen receptor from activating additional genes later in the process. Currently approved drugs cannot disable the receptor in this way.
In light of these discoveries, the biopharmaceutical company Medivation, Inc., licensed MDV3100 from UCLA in 2005, and, in 2007, the OHSU Knight Cancer Institute and other sites began enrolling men with CRPC who had relapsed after treatment with conventional hormone therapy in phase I and II clinical trials of MDV3100.
A total of 140 men participated in the nationwide study of MDV3100. They were divided into groups that received varying daily doses (30 mg to 600 mg) of MDV3100. Men were treated for as long as their cancer remained controlled and some remain on treatment today.
Results were encouraging at all dose levels:
• 56 percent of the men in the study saw their PSA levels drop by 50 percent or more.
• 22 percent of patients saw their tumors shrink.
• 49 percent of patients saw the disease stabilize in soft tissue.
• 56 percent of patients saw the disease stabilize in bone.
• 49 percent of all patients saw their circulating tumor cell (CTC) count turn from unfavorable to favorable.
• Of patients who began the study with favorable CTC counts, 91 percent retained favorable counts during treatment.
The most common adverse event was fatigue, which generally resolved with reductions in the dose of the drug. The most common mild side effects were nausea, constipation, diarrhea and anorexia. Two patients had experienced seizures and one additional patient had a possible seizure. Whether MDV3100 was responsible for these seizures is unclear, because both patients who had experienced seizures were concurrently taking drugs that could contribute to a lowered seizure threshold.
The Phase III trial of MDV3100 is open and under way at the OHSU Knight Cancer Institute.
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About Prostate Cancer
Prostate cancer is the most common non-skin cancer in the United States and the third most common cancer worldwide. More than 1 million men in the United States have prostate cancer. An estimated 192,280 new cases were diagnosed in 2009, and approximately 27,360 men died from the disease last year alone. Patients with castration-resistant (also known as hormone-refractory) prostate cancer have few treatment options and a poor prognosis.
About the OHSU Knight Cancer Institute Visit www.ohsuhealth.com/cancer
With the latest treatments, technologies, hundreds of research studies and approximately 400 clinical trials, the OHSU Knight Cancer Institute is the only cancer center between Sacramento and Seattle designated by the National Cancer Institute — an honor earned only by the nation's top cancer centers. The honor is shared among the more than 650 doctors, nurses, scientists and staff who work together at the OHSU Knight Cancer Institute to reduce the impact of cancer.
The Oregon Health & Science University is the state's only health and research university, and Oregon's only academic health center. OHSU is Portland's largest employer and the fourth largest in Oregon (excluding government). OHSU’s size contributes to its ability to provide many services and community support activities not found anywhere else in the state. OHSU serves patients from every corner of the state, and is a conduit for learning for more than 3,400 students and trainees. OHSU is the source of more than 200 community outreach programs that bring health and education services to every county in the state.