Each year, approximately 300,000 American patients suffer from bone metastases. These metastases contribute to significant morbidity and mortality in patients with advanced cancer. I, like many other patients, often wonder if i will find myself having to deal with this aspect of the disease.
At PCF’s 18th Annual Scientific Retreat last week, I was very encouraged to to see continued progress in better understanding the mechanisms of prostate cancer bone metastases and treating this painful and life-threatening manifestation of advanced disease. While attending the Retreat is always a bit like drinking from a fire hose, it is always an enlightening and impressive experience. Sitting in a room with more than 350 of the world’s brightest minds in cancer research can be every bit overwhelming as it is encouraging.
Since so many readers of this blog are currently having to deal with bone metastases, I decided to share what I learned about the advances being made in this area. (Several times each month, I hear from readers whose cancer has traveled to their bones.) In the first part of this report, you might be surprised to see where discovery can can take root… It’s a great example of PCF bringing people with unique expertise to contribute to our field. Dr. Taichman is a dentist-scientist whose discoveries are better informing better treatment strategies for prostate cancer.
Dr. Taichman has studied agents that coax invading prostate cancer cells from these bone niches and force them back into the blood stream where therapeutic agents can destroy them. These findings hold promising potential for the treatment of metastatic prostate cancer lesions by “kicking prostate cancer cells out of the hematopoietic stem cell nest” and letting the healthy normal blood stem cells have the nest back.
Alpharadin (radium-223 chloride) a promising new therapeutic—Oliver Sartor, MD, from Tulane University, provided Retreat attendees with an in-depth overview of the development of an exciting new therapeutic, Alpharadin (radium-223 chloride) which is about to be approved in Europe and the US. It is an investigational alpha-pharmaceutical (containing an alpha-particle-emitting nuclide) in development for cancer patients with bone metastases. This compound is “first in class” and is atomically like calcium. It mimics many of the behaviors of calcium including quick uptake into the bone, particularly where calcium is being deposited, in bone metastases.
In the Phase III clinical trials, Alpharadin improved overall survival by about 3 months for patients with castration-resistant prostate cancer and bone metastases without affecting patient’s bone marrow functions and forcing transfusions of platelets or red blood cells. Based on a recommendation by the Independent Data Monitoring Committee (IDMC), the clinical trial was stopped and patients on the placebo were given the option to receive the drug.
Alpharadin treatment is the first of its kind. By decaying radioactively in the bone metastatic site, Radium 223 fires off an alpha particle of energy that kills nearby prostate cancer cells. Alpharadin enters a patient’s bone and disperses small amounts of “short-range, high-energy” radiation, attacking the prostate cancer and preserving healthy cells surrounding the tumor. The Prostate Cancer Foundation was the first foundation to fund the proof of concept of radiopharmaceuticals at University of Texas MD Anderson Cancer Center through Dr. Christopher J. Logothetis using beta particles. When approved by regulatory agencies, Alpharadin will be the 5th new agent in a growing number of new drugs that have been approved for increasing survival of men with mCRPCA in the past 18 months. Alpharadin is intriguing as it could be combined with new immunotherapy approaches.
Studying XL184 (Cabozatinib) anticancer activity and its ability to shrink tumors in bone and soft tissue—PCF-funded investigators, Matthew Smith, MD, PhD, from the Massachusetts General Hospital Cancer Center and Phillip Febbo, MD, at UCSF, held a discussion on XL184.
Abnormal MET activation (a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor–HGFR) in cancer correlates with poor prognosis, where aberrantly active MET triggers tumor growth, formation of new blood vessels (angiogenesis) that supply the tumor with nutrients, and cancer spread to other organs (metastasis). Vascular endothelial growth factor (VEGFR2) is a central regulator of the angiogenic process in tumor angiogenesis and the proliferation of tumor cells. In early clinical trials, Cabozantinib (XL184), a dual inhibitor of MET and VEGFR2, has shown promising results in shrinking metastatic tumors in both bone and soft tissue in patients with advanced prostate cancer.
While most cancer therapies to date have modest effects on bone metastases, tumor shrinkage is observed in a majority of patients who are given Cabozantinib: at week 12, there was a 74% control rate of tumors in prostate cancer patients: complete or partial bone scan resolution in 85% of PCa patients; and stabilization was achieved in 13% of PCa patients. These positive results were accompanied by pain relief and impressive bone scan improvement and were observed in castrate-resistant prostate cancer as well as breast cancer, melanoma, renal cell carcinoma, and thyroid cancer.
While studies of the most effective dosing continue, patient tolerance of Cabozantinib is consistent with other tyrosine kinase inhibitors and its manufacturer, Exelixis is planning to initiate its first pivotal trial in castrate-resistant prostate cancer by the end of this year. Dr. Febbo provided his perspective on the mechanism of action of XL184. He suggested that both receptor tyrosine kinases, c-Met and VEGF-R2, are critical in bone metastases and, when their signaling is blocked together—with a single drug that acts on both—a therapeutic effect is achieved. Neither c-MET nor VEGF-R2 were implicated as central in treating bone metastatic disease 24 months ago in prostate cancer research and both now are the focus of intensive research funded by PCF.
Xgeva update—In related news, the use of Xgeva (denosumab) to prevent bone deterioration and fracture in patients undergoing hormone therapy (ADT) was approved by the FDA just days prior to the start of the Scientific Retreat. Approval of a second indication of Xgeva—to actually delay or prevent metastases to the bone—is currently under review. The FDA has indicated that it will make an approval decision by April 2012. Dr. Smith, who has long focused on improving survivorship in men with advanced disease, has led Xgeva studies over the past few years.
Read the complete post-Retreat Advances with more highlights from the meeting.