Takeda Oncology Company and Millenium announced recently that they are halting the development of TAK-700 (Ortoronel) due to poor Phase III trial results in men with metastatic prostate cancer who have not had previous chemotherapy. The drug failed to extend survival time. TAK-700 has been previously discussed in blogs published on this website on June 3rd and November 21st, 2011. TAK-700 is an oral, non-steroidal, androgen (e.g. testosterone) synthesis inhibitor. End points of the clinical studies also included delay in disease progression in addition to extending survival time.
It was recently announced that the Finnish drugmaker Orion Corporation and Bayer Pharmaceuticals have entered an agreement to jointly develop Orion’s ODM-201, an oral, androgen receptor inhibitor. Bayer and Orion plan to jointly start the clinical Phase III program in 2014 to further evaluate the efficacy and safety of ODM-201 in patients with non-metastatic castration (hormone)-resistant prostate cancer. These patients are at high risk of developing metastatic disease and can be identified due to rapid Prostate Specific Antigen (PSA) increases. Phase II clinical studies of ODM-201 demonstrated it to be efficacious and well-tolerated. Eighty-six percent of patients who had not received earlier chemotherapy or abiraterone (Zytiga) experienced a greater than 50% PSA decrease at week 12 on a dose level of 700 mg twice a day. ODM-201 disrupts a tumor cell’s ability to use testosterone by binding with high affinity to the androgen (testosterone) receptor (AR) protein on cells, thereby inhibiting its cellular function. The AR normally binds to testosterone (which fuels prostate cancer) inside the cell and ushers it into the cell nucleus where it enhances cell growth. ODM-201 has similar activity to the anti-androgen drug enzalutamide.
1) MRI or Ultrasound-Guided Biopsies; 2) Effect of Diet on Prostate Cancer; and, 3) Two Genes Linked to Aggressive Prostate Cancer.bjgabrielsen : June 27, 2014 4:12 am : 2014
1) A recent article was published from the Washington University School of Medicine which compared the results of prostate cancer biopsies as guided by magnetic resonance imaging (MRI) with those obtained via ultrasound guidance. It was concluded that MRI-guided biopsies were more likely to find aggressive tumors than those that rely on ultrasound. For specific details, see the following link.
2) Another article published in Medline Plus, described a Duke University study of the effects of diet and lifestyle on prostate cancer. A diet rich in complex carbohydrates and lower in protein and fat is associated with a 60 percent to 70 percent reduced risk of prostate cancer according to the researchers. In addition, a fiber-filled diet reduced the risk of aggressive prostate cancer by 70 percent to 80 percent. The presence of metabolic syndrome factors also increased the cancer risk. Metabolic syndrome consists of a group of risk factors that increase a person’s risk of heart disease, diabetes and stroke. They include obesity, high blood pressure, elevated blood sugar levels, elevated levels of triglycerides (blood fats) and reduced levels of “good” HDL cholesterol.
3) Lastly, Columbia University researchers have identified two genes that they claim “are likely driving the most aggressive cases of prostate cancer. Other scientists had linked the genes, FOXM1 and CENPF, to cancer, but had not connected them to prostate growths. And more importantly, it was observed that the two genes’ cancer-causing effects only occurred if they are turned on at the same time. These two genes individually don’t do anything, or very little, but only when they are co-active do they produce aggressive forms of the disease.” The presence of activity in these two genes could be determined at the time of a biopsy. “If both genes are turned on and highly active, then men would be advised to get immediate treatment such as surgery, radiation or tumor-targeting drugs, or some combination of these. If neither gene, or only one is active, then doctors might recommend less intensive therapy while they monitored the tumors” according to the researchers.
The Johns Hopkins Health Alerts are extremely informative about various health issues including prostate cancer. The latest alert (June 14th) discussed the Gleason Score, the most important factor in predicting the current state of a prostate cancer. The Gleason Score is based on tumor grade, which is an indication of the tumor’s aggressiveness. The tumor grade reflects how far the cancer cells deviate from normal healthy cells. See the link for the full article.
Exercise and Prostate Cancer; Enzalutamide Extends Survival; and, Synergy in Cancer Risk Assessment.bjgabrielsen : June 19, 2014 5:54 pm : 2014
Several articles of interest were recently published in the February-March, 2014 NewsPulse from the Prostate Cancer Foundation (PCF). This information had been presented at the American Association for Cancer Research (AACR) meeting. The first article described the benefits of exercise in men prior to their prostate cancer diagnosis as well as during therapy for their condition. A second article cited a new study involving 1700 men who received a new, oral hormone therapy drug, enzalutamide. The treatment increased survival by 29% and delayed disease progression by 81% in men with advanced prostate cancer who had become resistant to standard hormonal therapies and who had not received previous chemotherapy. In 2012, the U.S. Food and Drug Administration had approved enzalutamide for use in prostate cancer patients who had received prior chemotherapy. Enzalutamide is a type of hormonal therapy that blocks the androgen (male hormone) receptor on cells. In addition, treatment with enzalutamide delayed the need for chemotherapy by 17 months. A third article described how combining clinical information from the CAPRA score with the genetic information expressed in either of the Oncotype DX or Prolaris assays yielded improved prostate cancer risk assessment and reduced overtreatment. These results were better than results achieved with either clinical or genetic information alone. A CAPRA score is a means to predict whether a patient has low, intermediate, or high risk prostate cancer; the scores generated are used to guide treatment decisions. CAPRA scores integrate PSA levels, Gleason score, clinical T stage, patient age, and the percentage of prostate biopsy tissue containing malignant cells. This methodology is 80% accurate in predicting the likelihood of progression to fatal disease.
It is widely accepted that selected genetic screening is the future of prostate cancer detection. Two interesting articles were recently published describing such screening involving the aggressive breast cancer genes, BRCA1 and BRCA2 among others (CHEK2, PALB2 and ATM). For details, see the following link. In addition, researchers in the United Kingdom have determined that advanced prostate cancer can been linked to mutations in eight genes.
A multi-center study from the Fred Hutchinson Cancer Center in Seattle and published in the Journal of the National Cancer Institute have shown that vitamin E can heighten the risk in men with low baseline selenium levels. In addition, selenium supplements can raise the prostate cancer risk in men with high baseline levels of the trace element. The researchers concluded that their study showed no benefits to any man from either selenium or vitamin E supplements and for a significant number of men, these supplements were actually harmful. For more details, see the following link.
To improve the accuracy of PSA values in the diagnosis of prostate cancer, PSA density and PSA velocity are useful concepts. PSA density takes into account the size of a man’s prostate gland when evaluating his PSA level. It is calculated by dividing the PSA value by the size of the prostate as determined by ultrasound. The numerical range of values is useful in differentiating prostate cancer from an enlarged benign prostate. Studies conclude that a PSA density value of greater than 0.15 indicates a higher cancer risk. In my own case, this value was useful in my cancer diagnosis since my prostate was not enlarged yet my PSA was in the high normal range. On the other hand, PSA velocity takes into account changes in a man’s PSA values over time which rise more rapidly in men with prostate cancer than in those without the disease. For more information and a summary of numerical values for PSA density and PSA velocity see the May 28th, 2014 article in Prostate Disorders from the Johns Hopkins Health Alerts.
A “Buffet” of Prostate Cancer News Items; Hormonal and Radiation Therapy, Younger Patients and the Effects of Statin Drugs.bjgabrielsen : May 19, 2014 1:48 am : 2014
1) Intermittent Hormonal Therapy: Prostate cancer is often kept “under control” by depriving the cancer cells of their “fuel”, namely androgens such as testosterone or dihydrotestosterone. Androgen deprivation (hormonal) therapy (ADT) is often applied on an intermittent basis the goal of which is to minimize potentially harmful side effects. The May 11th edition of the Johns Hopkins Prostate Disorders Health Alerts contained an excellent overview of intermittent androgen suppression.
2) Why Androgen Deprivation Enhances Radiation Therapy: It has been known since 2011 that adding a short course of androgen deprivation therapy (ADT) to radiation therapy in prostate cancer patients increased their chances for survival. Recent research indicates that the rationale for this combination treatment lies in the fact that ADT retards the ability of cancer cells to repair DNA damage caused by the radiation therapy thus leading to their programmed cell death or apoptosis. One such DNA repair enzyme is called DNAPK which may be a good target for antitumor drug development. Inhibitors of a similar single-strand DNA repair enzyme, PARP1 [(polyADP-ribose) polymerase], are currently being evaluated in Phase III clinical trials involving breast and ovarian cancers. (PARP1 inhibitors seem to have a beneficial effect on women with a specific BRCA breast cancer genetic mutation.) The relationship between the androgen receptor (AR) and DNA repair proteins such as DNAPK is also summarized in the March 31st issue of the Prostate Cancer Foundation (PCF) NewsPulse.
3) A Study Comparing “Watchful Waiting” versus Surgery in Younger Prostate Cancer Patients: A joint Swedish – Harvard life expectancy study of 700 men with early prostate cancer and published in the March 6th New England Journal of Medicine concluded that surgery (radical prostatectomy) may “trump” watchful waiting in younger men diagnosed with prostate cancer. A summary of this study and comments by other researchers was published in the March 31st issue of the Prostate Cancer Foundation (PCF) NewsPulse.
4) The Effects of Statin Drugs On Prostate Cancer: The March 31st PCF NewsPulse also contained a review of various studies related to the effects of cholesterol-lowering statin drugs on prostate cancer. Researchers conclude that statins do not have an effect on the incidence of prostate cancer however prolonged use may lower the risk of advanced disease and death. No protective effects from statins have been observed and there does not seem to be any association between statin use and early incidence of prostate cancer. Current research is focused on where statins may play a role in the overall prostate cancer cycle.
Four Clinical Trials Involving Focal Therapy for Prostate Cancer Patients Who are Low-Risk or Under Active Surveillance.bjgabrielsen : May 9, 2014 5:09 am : 2014
The Prostate Cancer Research Institute (PCRI) recently published details of four (4) clinical trials which are recruiting low-risk prostate cancer patients or those currently under active surveillance. Low-risk determination is based upon PSA, Gleason score, and clinical stage. The treatments offered are referred to as “focal therapy” wherein a portion of the prostate is being treated instead of the entire gland. The clinical trials include brachytherapy (radioactive seeds), laser (interstitial thermal therapy) and high intensity focused ultrasound (HIFU). Details concerning location, eligibility criteria, and contact information are provided in the PCRI link. Clinical trial locations include Memorial Sloan Kettering in New York, University of Chicago, Mayo Clinic, City of Hope, and Desert Medical Imaging (California). Three of these studies involve MRI-guided therapies.