Abiraterone Acetate (Zytiga) Approved to Treat Hormone-Refractory Prostate Cancer Before Chemotherapy.bjgabrielsen : December 12, 2012 9:43 pm : 2012, Treatment Information
In the past, when a prostate cancer patient became non-responsive (refractory) to hormonal therapy, the next step in his treatment was chemotherapy with taxotere (docetaxel). This treatment was usually accompanied by significant side effects. Meanwhile, in April, 2011, the Food and Drug Administration (FDA) had initially approved abiraterone acetate (Zytiga) for use in patients whose prostate cancer had progressed after chemotherapeutic treatment with taxotere. But on December 10th, 2012, the FDA expanded the approved use of abiraterone before chemotherapy for men with hormone-refractory, metastatic prostate cancer.
Testosterone stimulates the growth of prostate tumors, so drugs such as Lupron used in hormonal therapy or surgery that reduces testosterone production or blocks testosterone’s effects are used to slow the growth of prostate cancer. However, most prostate cancers eventually become resistant to these treatments. These resistant cancers continue to grow even when levels of testosterone are very low. Abiraterone is a pill that treats tumors by reducing testosterone production by inhibiting the production of androgen (testosterone) in the testes, adrenal glands, and prostate cancer tumors themselves.
Abiraterone’s safety and effectiveness for its expanded use were established in a clinical study of 1,088 men with late-stage, hormonal-resistant prostate cancer who had not previously been treated with chemotherapy. Participants received either abiraterone or a placebo (both in combination with the corticosteroid prednisone). The study was designed to measure the length of time a patient lived before death (overall survival) and the length of time a patient lived without further tumor growth as assessed by imaging studies (radiographic progression-free survival, or rPFS). Patients who received abiraterone had a 25 percent decrease in the risk of death. Study results also showed abiraterone improved rPFS. The median rPFS was 16.5 months for patients treated with abiraterone versus 8.3 months in the placebo group.
The most common side effects reported included fatigue, joint swelling or discomfort, swelling caused by fluid retention, hot flashes, diarrhea, vomiting, cough, high blood pressure, shortness of breath, urinary tract infection, and bruising. The most common laboratory abnormalities included low red blood cell count; high levels of the enzyme alkaline phosphatase, which can be a sign of other serious medical problems; high levels of fatty acids, sugar, and liver enzymes in the blood; and low levels of lymphocytes, phosphorous, and potassium in the blood. For further information, see the FDA update section in the December 11th, 2012 issue of the National Cancer Institute (NCI) Bulletin.
In the last weeks, information about the use of Zytiga has been published in several sources. Among them, the Prostate Cancer Foundation (PCF) Newsletter of December 19th, 2012 described the approval of Zytiga as one of the main breakthroughs of 2012. The December 13th, 2012 edition of the ZeroHour Newsletter (from Zero-The Project to End Prostate Cancer) also reprinted an article about approval of Zytiga. Finally, the news was also published in the Dec. 13th issue of the Prostate Cancer Research Institute (PCRI) Weekly.
The National Cancer Institute (NCI) is the largest of the numerous institutes comprising the National Institutes of Health (NIH) in Bethesda and Frederick, Maryland. The NCI publishes a monthly cancer bulletin focused on all types of cancer. The current special issue (NCI Cancer Bulletin, Vol. 9, November 27th, 2012) is specifically devoted to cancer screening. Screening is an important part of the effort to reduce the number of lives lost to cancer. A tremendous amount of research is currently focused on improving the effectiveness and efficiency of cancer screening. Some studies suggest that about one-third of screen-detected localized breast cancers and up to 70 percent of localized prostate cancers are overdiagnosed. As more has been learned about the benefits and harms of PSA screening for prostate cancer, organizations have begun to recommend against routine screening. Screening is a personal decision that, according to most experts, a man should make in consultation with his doctor, after he has been informed in detail about the potential benefits and harms. An infographic published in the latest NCI Cancer Bulletin depicts the benefits and harms of PSA screening for prostate cancer. The estimates appeared in the U.S. Preventive Services Task Force Recommendation Statement, published July 17 in the Annals of Internal Medicine. The estimates were based on 13- and 11-year follow-up data from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial and the European Randomized Study of Screening for Prostate Cancer. According to the two trials, the best evidence of possible benefit of PSA screening is in men aged 55 to 69.
If prostate cancer is diagnosed, active surveillance is recommended by the National Comprehensive Cancer Network as a first-line option for older men at very low or low risk of developing advanced prostate cancer. Findings from the Johns Hopkins active surveillance program — the largest and longest-running in the world — provide important insights. It should be noted that Johns Hopkins Urology has been consistently rated #1 in the annual U.S. News and World Report survey and review. “In one promising development, researchers were able to identify risk factors present at diagnosis and the first surveillance biopsy that were associated with disease progression and to use that information to restratify men into new risk categories. This strategy will make it possible for doctors to predict earlier and more accurately the likelihood that the prostate cancer will progress after a man enters the surveillance program. Even when a cancer appears to be low risk, there is always a chance that it will grow and become more aggressive. One challenge is to determine the mathematical likelihood of that happening. To that end, researchers at Hopkins have been using a mathematical formula that helps predict which men in the active surveillance program will need treatment. Called the Prostate Health Index, or PHI, this mathematical equation takes into account PSA, percent-free PSA, and proPSA (a variant of PSA that increases in men with prostate cancer).” This and other valuable information can be obtained by subscribing on-line to the Johns Hopkins Prostate Disorders Health Alerts written by Drs. Jacek Mostwin and H. Ballentine Carter. The most recent issue was published on November 22, 2012. On a personal note, I personally have interacted with Dr. Mostwin for the past seventeen years and recommend him most highly. Dr. Carter is also highly esteemed.
At some point in life, all of us will be diagnosed with a serious and perhaps life-threatening medical condition. How will we react in such a situation? Could such an unwanted circumstance have a deeper purpose? A difficult diagnosis and illness can be viewed as either a mirror or a window. A dark adversity can represent a mirror in which we see ourselves and then are overcome with self-pity. Alternatively, a difficult time as this can be a window through which we can see the world around us filled with people who are walking a similar pathway as ourselves. An important purpose for which God can use our specific condition is found in the Bible in 2 Corinthians 1:3-4 which states: “All praise to God, the Father of our Lord Jesus Christ. God is our merciful Father and the source of all comfort. He comforts us in all our troubles so that we can comfort others. When they are troubled, we will be able to give them the same comfort God has given us.” Our condition can serve as a major purpose in ministering to others experiencing similar situations. A man whose wife was dying of cancer has shared his thoughts* based on Psalm 55. As he witnessed the fourth member in a family of four facing a battle with cancer, he was strongly reminded of Jesus’ experience and prayer in the Garden of Gethsemane just prior to his crucifixion. Jesus had been betrayed by Judas, denied by Peter and forsaken by all His disciples. Jesus’ response was to cast His burden on God the Father thus serving as an example for us all when we are distressed or when we are helping to comfort others.
The starting point for all of us including Jesus is to pray that our suffering be removed and that we be delivered of our condition. Jesus prays in Matthew 26:39, “He went a little farther and fell on His face, and prayed saying, ‘O My Father, if it is possible, let this cup pass from Me; nevertheless, not as I will, but as You will.” After praying for deliverance, Jesus’ second prayer was for acceptance when He prayed in verse 42, “O My Father, if this cup cannot pass away from Me unless I drink it, Your will be done.” For me personally, this is the most difficult prayer to pray yet it is the prayer that God wants to hear above all others as it demonstrates our complete faith and trust in God’s overall plan for our lives and the events therein. The third level of Jesus’ prayer (and ours hopefully) is one of glorification. Jesus desired that God’s grace would be seen in Him and that His Father would be glorified. In John 12:27-28, Jesus prays “Now my soul is troubled and what shall I say? ‘Father, save Me from this hour?’ But for this purpose I came to this hour, Father, glorify Your name.” The beauty of Jesus’ prayers is that they not only reveal His divine nature but His human nature as well. He is fully capable of truly “feeling our pain.” We too can cast our burdens on the Lord and in the process help others to do so as well. May our deepest desire be that God’s grace would be seen in us, that we share with others the comfort which we ourselves have received, and that God would be glorified in our stressful times and in our reaction to them.”
* Adapted from “When You Feel Like Running Away: Psalm 55” by Roy Clark. © 2008 RBC Ministries.
An extremely useful article was recently published by Nathan Roundy in the August, 2012 issue of the Prostate Cancer Research Institute (PCRI) Insights. The article is directed toward men who have been recently diagnosed with prostate cancer. It defines various medical terms and diagnostic and treatment details. Risk assessment tools are provided to help one determine whether the cancer is of low, intermediate or high risk. These tools include brief discussions (with website references) of risk stratification methods as published by Dr. Anthony D’Amico in 1998; a schematic prostate cancer guideline summary published by the National Comprehensive Cancer Network; the CAPRA risk score based on statistical outcomes from over 10,000 men; and, the PCRI SHADES risk tool. An extremely useful Risk Analysis Data Form is also included (and can be downloaded). This form contains a series of fourteen questions and related medical information to be provided during visits with one’s urologist. This article is an excellent initial reference for anyone newly diagnosed with prostate cancer. The document is only intended to assist the prostate cancer patient to understand their diagnosis and to outline questions and issues to be discussed with one’s urologist. It should never be considered as actual medical advice.
The PCRI Insights are published quarterly and comprise highly-recommended reading for any prostate cancer patient. The August 2012 issue also features a patient’s experience with the process of active surveillance of his cancer.
It would be useful if one could detect and identify the location of localized prostate cancer recurrences and metastatic disease in early PSA recurrence in men who had previously failed initial cancer treatments. For example, such identified “focal” or local recurrences in 1-2 specific areas of the body could then be treated surgically or with targeted radiation. These areas of recurrence might not have been detectable by bone, CT or other scanning methods alone. Physicians at the Mayo Clinic in Rochester, Minnesota and at the Arizona Molecular Imaging Center in Phoenix, Arizona describe the use of positron emission tomography (PET)/CT scanning to identify such localized areas of recurrent prostate cancer in men who have failed surgery, radiation, hormonal and/or chemotherapies. The specific tumor-targeting agents are C-11 choline and C-11 acetate administered intravenously. These radioactive agents emit positrons (positively-charged electrons) over a short period of time; their half-life is about 20 minutes. Therefore, the agents have to be prepared in an on-site cyclotron just prior to their use. In preliminary results reported in the August, 2012 issue of the Prostate Cancer Research Institute (PCRI)Insights, Arizona researchers report an overall detection rate of 85% for recurrent or metastatic disease using C-11 acetate PET/CT imaging. Detection was followed by radiation therapy or surgical removal of the identified lesion. Access to C-11 acetate requires participation in an approved clinical study. For information about participating in this on-going Phase II clinical trial see the ClinicalTrials.gov website at http://clinicaltrials.gov/ct2/show/record/NCT01304485. The C-11 choline agent available at the Mayo Clinic has already been approved by the Food and Drug Administration (FDA) as an agent for prostate cancer imaging. It has demonstrated accuracy in detecting lesions in both bone and lymph nodes. Examples of its usefulness are provided in a 17-minute video presentation given by Mayo’s principal investigator, Dr. Eugene Kwon. Both of these studies are relatively small in scope. The usefulness of this technique rests on its ability to identify the specific location of localized cancer recurrences and then the ability to treat them surgically or with radiation. The PET/CT imaging therapy described above would not be applicable to systemic disease covering multiple areas of the body. Its value would be in cases where recurrent tumors / metastases could be identified and localized in a specific area of the body which would allow the tumors to be removed surgically or with radiation.
While PET/CT imaging is not currently widely accessible, it may be very useful in specific cases. On a personal note, I know of a prostate cancer patient who might well have benefitted from the techniques described above. He had undergone a seemingly-successful radical prostatectomy. His PSA remained undetectable for about eight (8) years. Shortly thereafter, he began to experience a strong pain in his lower back / spinal area. X-rays, bone and CT scans were inconclusive in determining the origin of his pain. Meanwhile, his PSA escalated very rapidly to 25 ng/dL. An MRI revealed a mass in his lower back/spine which was removed surgically within two days of diagnosis. The patient’s PSA has been undetectable for the last two years.
Xtandi (Formerly MDV3100) Approved by the FDA for Treatment of Hormone- and Chemotherapy-Resistant Prostate Cancers.bjgabrielsen : September 14, 2012 4:07 am : 2012, Treatment Information
On August 31st, 2012, the Food and Drug Administration (FDA) approved MDV3100 (now known as Xtandi) for treatment of prostate cancers in men who have previously failed hormone and chemo therapies. (See the full story in the August 31st issue of the Prostate Cancer Foundation, PCF, NewsPulse). In its Phase III clinical trials, Xtandi increased median survival by 4.8 months (18.4 versus 13.6 months) over patients receiving the placebo. Overall, some patients had lengthy remissions well beyond the average time while others did not respond. These positive results led to the Phase III clinical trial being stopped early and the drug then being offered to patients in the placebo arm of the study due to its effectiveness in causing remissions and its high patient tolerability. [This was also the case during the Phase III clinical trials for Zytiga (abiraterone acetate) in 2011.] Xtandi has a novel mechanism of action. It does not shut off the production of testosterone but instead blocks testosterone’s effects by directly blocking the activity of the androgen (hormone) receptor at three distinct points, thus interfering with the “engine” of prostate cancer progression. By comparison, Zytiga affects cancer progression by shutting off the cell’s supply of testosterone, the “fuel” that drives the “engine”. Both Zytiga and Xtandi are administered orally and are currently being evaluated in Phase III trials in patients who have failed hormone therapy but have not yet received chemotherapy. Further efforts will concentrate on testing both drugs in men with early recurrence of prostate cancer. In addition, both drugs are also being tested in a pre-surgical condition, prior to prostatectomy, with the intent of potentially curing primary, high-risk prostate cancer. Having both drugs available represents an important advance in patient treatment. The nine-year research and development period for Xtandi has been relatively short when compared to twelve years or more for other drugs. Xtandi will be distributed jointly by its co-developers, San Francisco’s Medivation, Inc. and the Japanese company, Astellas Pharma, Inc.
An Example of Potential New Prostate Cancer (PC) Treatments on the Horizon. Killing PC Cells With Radioactive Gold Nanoparticles Containing a Component of Tea as the Targeting Agent.bjgabrielsen : September 4, 2012 3:44 am : 2012, Treatment Information
Nanotechnology is finding potential applications in many areas of our lives including cancer. [A nanometer is defined as one billionth of a meter or one ten millionth of a centimeter (there are 2.54 centimeters per inch).] Synthetic nanometer-sized particles (such as atoms, molecules or fragments thereof usually less than 100 nanometers in size) are being used in many areas of current research including the medical sciences, electronics, optics, magnetics, information technology and materials development. An article recently appeared in the July 16th, 2012 Proceedings of the National Academy of Sciences (PNAS) which described the injection into mouse prostate tumors of nanoparticles consisting of an isotope of radioactive gold (Au -198, used to destroy the tumor) coupled with a compound found in tea (epigallocatechin gallate, EGCg), used to specifically target the nanoparticle to prostate cancer cells. This type of therapy could minimize many of the potential side effects from current modes of chemotherapy. The radioactive gold-198 isotope releases beta-particles (streams of electrons) which are stopped very easily by an adjoining barrier thereby killing nearby tumor cells without penetrating surrounding normal tissues. The radioactive gold-198 loses its radioactivity within three weeks. The particles were just the right size such that they remained within the tumor once it was reached with the help of the EGCg compound from tea which has an affinity for prostate cancer cells (specifically laminin67R receptors which are over-expressed in prostate cancer cells). Tumor volume was reduced in mice by approximately 80% and nearly 75% of the nanoparticles remained trapped in the prostate gland after injection. A description of the research also appeared in the August 14th, 2012 Nanotech News. Since these initial results were in mice, further preclinical work is needed before any potential application in humans. However, it demonstrates a new method of chemotherapy for prostate and other solid tumors using specifically-targeted nanoparticles. The work was supported in part by the National Cancer Institute (of the National Institutes of Health , NIH) Alliance for Nanotechnology in Cancer.
A recent study from Johns Hopkins University School of Medicine published in the Journal of Clinical Oncology concluded that for men over 65 “active surveillance is the first option for men in this category with very-low-risk disease” according to senior investigator Dr. H. Ballantine Carter. The initial question for such patients should be “whether any therapy is appropriate for them, not which therapy.” The clinical definition of “very-low-risk prostate cancer is provided in the article initially published in the April 19th, 2011 issue of the National Cancer Institute (NCI) Cancer Bulletin. At Johns Hopkins, the active surveillance program involves a semi-annual check up and an annual biopsy. Among the 769 men enrolled in the Hopkins active surveillance program from 1995-2010, approximately 80% had very-low-risk disease as defined by their Gleason score and other factors listed. Overall, 41% of the men in this study did not require any form of treatment even after ten years of follow-up, providing evidence that “active surveillance” is safe. For additional information, see the July 24th, 2012 issue of the NCI Cancer Bulletin.
The American Society of Clinical Oncology (ASCO) is a highly respected organization. On July 16th 2012, a committee of experts from ASCO published a provisional clinical opinion regarding PSA screening in the Journal of Clinical Oncology. This information is also summarized in the July 24th, 2012 issue of the National Cancer Institute (NCI) Bulletin. Briefly, ASCO experts concluded that for men with a life expectancy of 10 years or less, “it is recommended that general screening for prostate cancer with total PSA be discouraged, because harms seem to outweigh potential benefits.” However, for men with life expectancies of greater than ten (10) years, “it is recommended that physicians discuss with their patients whether PSA testing for prostate cancer screening is appropriate for them. PSA testing may save lives but is associated with harms, including complications, from unnecessary biopsy, surgery, or radiation treatment.” Thus younger men may have meaningful benefits from PSA screening but this can be accompanied by a risk of harms. These aspects must be balanced in order to arrive at a plan of action if warranted.
The National Cancer Institute (NCI), the largest of the institutes comprising the National Insitutes of Health (NIH) in Bethesda and Frederick, Maryland is sponsoring a clinical trial for men who have slow-growing prostate cancer confined to a small portion of the prostate gland (low-volume disease). In this pilot study which is being conducted at the NIH Clinical Center, “men diagnosed with low-risk prostate cancer and men with suspected prostate cancer will undergo advanced magnetic-resonance imaging (MRI) techniques developed at NCI to visualize the prostate and tumor tissue in high detail and guide a biopsy to that area. The men will then be treated at a later date using MRI-guided focal laser ablation therapy to only the area of the prostate that has cancer.” Guided by MRI, a laser fiber will be inserted into the tumor nodule and used to locally heat the tumor. MRI will be used to watch in real-time as the heat from the laser destroys the tumor while leaving the remaining prostate gland intact and surrounding nerves and muscles controlling urination and erections unharmed. This study will assess the feasibility and safety of this therapy intended to treat only the area of the prostate where the tumor is located. For more information, see the article from the July 10th, 2012 issue of the NCI Cancer Bulletin.