Category: Treatment Information
Xtandi (Enzalutamide) Now Approved for Metastatic, Hormone-Refractory Prostate Cancer Before Chemotherapy.
The following is an important blog in three sections. It describes another approved therapeutic agent for men with metastatic, hormone-refractory prostate cancer. Also included are important discussions regarding the need for future clinical studies to maximize cancer remissions and overall survival.
In 2012, the Food and Drug Administration approved Xtandi® (enzalutamide) for men with metastatic, hormone-refractory prostate cancer who previously had undergone chemotherapy with taxotere (docetaxel®). This month, however, the FDA approved Xtandi® for use in the same patients before they had been treated with chemotherapy, thus creating one more option for men. Xtandi® is a second line hormonal therapy administered orally once daily which can suppress testosterone at three different sources giving many men an additional cancer response after initially failing hormone therapy. The November 2012 issue of the Prostate Cancer Research Institute (PCRI) Insights contains a very informative article by Dr. Neal Shore summarizing the use and mechanism of action of Xtandi®. The reader is advised to see the 2012 link at this point.
The second article by Dr. Mark Scholz is a blog from the February 2014 meeting of genitourinary section of American Society of Clinical Oncology (ASCO). Dr. Scholz mentions that Xtandi® (also formerly known as MDV3100 during its developmental stage) has been shown to extend life in both cohorts of prostate cancer patients discussed above. For specific details of the PREVAIL study, see the linked blog. Xtandi® now joins Zytiga® (abiraterone acetate) and Provenge® as therapeutic options for men before administering chemotherapy with taxotere. The question is now raised as to the optimal way to sequence administration of these agents. Dr. Scholz makes an argument that Provenge® which works by stimulating the immune system, should be administered first. After Provenge®, it is specially noted that the anticancer effects of Xtandi® is reduced when administered after Zytiga® and vice versa. This progressively increasing cancer resistance is not surprising. No data is currently available on the effect of sequencing these therapies on overall survival. Comparative studies and studies involving combination therapies are in order.
The third portion of this post are two very informative videos from Dr. Charles “Snuffy” Myers wherein he discusses the PREVAIL study results and prostate cancer remissions in general. In the first video, Dr. Myers notes the significant delay in radiological progression (e.g. bone, lymph node metastases) demonstrated by Xtandi® (11.2 months vs. 2.8 months for placebo). This will enable Xtandi® to be recognized as a first choice option for therapy. However, in the PREVAIL study, the overall survival result was less dramatic; only 2.2 additional months for Xtandi®. Dr. Myers poses the question of how a therapeutic agent can delay metastases yet minimally affect survival time. He notes it may take a long time to observe the effects of a drug if one is basing the effects on following PSA changes alone. The PSA can increase while the whole cancer is responding. Hence, one should not overly depend on PSA. Instead he proposes using alkaline phosphatase and the circulating tumor assay (CTC) as better markers. Insurance coverage is also discussed. One needs to have a complete remission in order to see significant survival effects. It is rare to observe remissions from a single agent. Studies involving combination therapies are needed. Dr. Myers suggests that studies involving sequential single agents may not be the best, but combination studies are needed to witness overall survival benefits. The second video mainly discusses the mechanism of action of Xtandi®, its safety profile and potential side effects. Dr. Myers notes that under 20% of patients receiving Xtandi® in the PREVAIL study went into complete remission. It is more safe and effective than casodex (liver damage). The major side effect is fatigue. Four-six weeks are needed to reach a therapeutic drug level and 2-3 months are required to see a clinical benefit. The unique mechanism of action of Xtandi® may also require changes in other drugs being taken by a patient.
A Phase III Trial Involving Enzalutamide in Men with Metastatic, Hormone-Resistant Prostate Cancer.
The Alliance for Clinical Trials in Oncology is conducting a Phase III clinical trial of enzalutamide (Xtandi®) with or without abiraterone acetate (Zytiga®) and prednisone in men with hormone-refractory, metastatic prostate cancer with the hope of improving overall survival. Details of this trial can be found at the U.S. National Institutes of Health (NIH) clinical trials website, ClinicalTrials.gov. Enzalutamide works by disrupting a tumor cells’ ability to use testosterone by blocking the cell’s testosterone receptors and prevents the production of androgens within the cell itself. Zytiga® inhibits two distinct steps in the production of testosterone from cholesterol even in tumor cells by blocking a cell membrane enzyme called CYP17A1. Both drugs have been approved by the Food and Drug Administration for treatment of men with metastatic, hormone-refractory prostate cancer. For further information on these two agents, see the January 3rd, 2012 website blog.
Affinity: A Phase III Trial Using Custirsen and Jevtana® for Men with Metastatic Hormone-Resistant Prostate Cancer.
The goal of the Phase III Affinity Trial is to test whether adding an experimental drug called custirsen to Jevtana® (cabazitaxel) chemotherapy can help treat men with hormone-resistant prostate cancer. In the latter case, chemotherapy with taxotere (docetaxel®) or Jevtana® (cabazitaxel) are often the first lines of chemotherapy adminstered. However, they are often accompanied by undesirable side effects and patients may eventually become resistant to the treatments. The current trial will examine whether adding the drug custirsen to the treatment with Jevtana® can help slow the progression of the prostate cancer. Custirsen is an experimental drug designed to block the production of a protein (clusterin) associated with treatment resistance in many cancers. Phase 2 trials suggest that custirsen may improve overall survival for patients with prostate cancer. While Jevtana® has been approved by the Food and Drug Administration, custirsen has not yet been approved. For additional details, see the following link to the Affinity trial as well as the January 3rd, 2012 website blog describing various prostate therapies in differing stages of clinical development.
PROSPECT: A Phase III Clinical Trial of the Immunotherapy Vaccine Prostvac in Asymptomatic Hormone-Resistant Prostate Cancer Patients.
The goal of the Prospect Trial is to enhance a man’s immune system to fight prostate cancer. It is a Phase III trial for metastatic, hormone-resistant prostate cancer patients who are either asymptomatic or minimally symptomatic. The trial utilizes the investigational immunotherapy, Prostvac, a therapeutic pox virus cancer vaccine directed at PSA-producing cells. It is administered with or without GM-CSF (granulocyte macrophage colony-stimulating factor). GM-CSF is a protein secreted by immune system cells that functions as a white blood cell growth factor. Prostvac is delivered via a series of injections over five months. The end point of the trial is to improve overall survival. Prostvac was developed at the National Cancer Institute (NCI), the largest of the institutes of the National Institutes of Health (NIH), Bethesda, Maryland. There is considerable interest in administering this vaccine to men in earlier stages of their disease. For more information such as concerning qualification and locations of the trial, see the following link. One can also find information at the National Cancer Institute’s clinical trial website, http://www.cancer.gov/clinicaltrials or call the NCI’s help line at 1-800-4-CANCER. Prostvac was also discussed in earlier blogs posted on this website on Sept. 20th, 2011, January 3rd, 2012, and the Bavarian Nordic website, who are co-developers of Prostvac. For a fact sheet on Prostvac and its results in previous trials, see the following link.
TAK-700 Development Halted Due to Poor Phase III Trial Results.
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.
New Prostate Cancer Drug, ODM-201, to Enter Phase III Clinical Trials.
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.
Exercise and Prostate Cancer; Enzalutamide Extends Survival; and, Synergy in Cancer Risk Assessment.
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.
A “Buffet” of Prostate Cancer News Items; Hormonal and Radiation Therapy, Younger Patients and the Effects of Statin Drugs.
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.
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.