The January 3rd, 2012 blog post lists prostate cancer drugs and therapeutics either currently approved by the Food and Drug Administration or under late stage clinical development. This listing is updated constantly as developments are disclosed. The latest update was posted on July 10th, 2012. Such future updates will be noted on the website home page.
Category: 2012
MDV3100 (enzalutamide) Now Available in Eleven (11) States.
The progress of developing new treatments for advanced prostate cancer continues. MDV3100 (now called enzalutamide) is being developed by Medivation Inc. and Astellas Pharma Inc. It is now available in eleven states as part of additional clinical trials in prostate cancer patients who have failed hormonal therapy and who have been previously treated with docetaxel (taxotere). Enzalutamide (MDV3100) had earlier demonstrated positive Phase III clinical trial results in men with hormone-refractory prostate cancer who had or had not undergone chemotherapy with taxotere (docetaxel). On this basis, it had been placed on a fast-track for approval by the Food and Drug Administration. The drug works by disrupting a tumor cells’ ability to use testosterone by blocking the cell’s testosterone receptors thus preventing the production of androgens (testosterone) within the cell itself. It is an oral, androgen receptor antagonist and does not require co-administration of steroids such as prednisone. For further information, see the clinical trial information found in this link. MDV3100 is included on a list of prostate cancer treatments under development and has been posted on this website in the 2012 blog dated January 3, 2012.
The U.S. Preventative Services Task Force Advises Against PSA Screening; a Summary of Responses.
Since its October, 2011 initial advisory, and after receiving input from the medical community including many leading urologists and oncologists, the United States Preventative Services Task Force (USPSTF) recently issued its final recommendation against screening asymptomatic men for prostate cancer using the prostate-specific antigen (PSA) test. (An earlier 2008 recommendation had advised against screening men over the age of 75.) The USPSTF conclusions are discussed in the May 29th, 2012 issue of the National Cancer Institute Bulletin among other sites below. The USPSTF panel concluded that routine diagnostic PSA screening could not be clearly demonstrated to save lives and its potentially-significant harms (such as false positive results, biopsy-related infections, potential incontinence and erectile dysfunction) outweigh any small potential benefits. However, PSA testing will still be used to monitor progression of prostate cancer after its diagnosis or treatment. Medicare is expected to continue to pay for such PSA evaluations. It must be noted that the USPSTF did not include any urologists nor medical oncologists on their panel. For a full listing of the Task Force members, their affiliations and their specific fields of expertise see http://www.uspreventiveservicestaskforce.org/members.htm. Strong criticisms of this recommendation have been issued by noted American urologists as well as medical and professional organizations such as the American Urological Association and the National Comprehensive Cancer Network. Additionally, a dissenting opinion was published in the Annals of Internal Medicine by some of the leading clinical scholars in prostate cancer care, including Dr. William Catalona, Medical Director of the Urological Research Foundation and Dr. Patrick C. Walsh, University Distinguished Service Professor of Urology at Johns Hopkins. These experts believe the USPSTF overestimated the harms and underestimated the benefits of PSA screening in the United States. Much of the discussion centered upon two separate clinical trials; the National Cancer Institute (NCI)-funded Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC). A recent study involving 20,000 Swedish men over a 14-year period has been cited as strong evidence that PSA screening does indeed save lives. (See the May 29th issue of the ZeroHour Newsletter). For an overview of affirming and dissenting opinions from various groups, see the Prostate Cancer Research Institute (PCRI) Weekly for May 30th, or the May, 2012 PCRI NewsPulse.
In light of these new recommendations, what should a man do at this point? The most important need is a shared decision-making process between a man and his trusted physician. Individual patient factors such as age, medical condition, symptoms (or lack thereof), family history, ethnicity or concerns about prostate cancer must form the basis of a rational decision between a patient and his physician to undergo PSA testing. As stated in the Prostate Cancer Foundation Newsletter, “the USPSTF’s position provides a teachable and actionable moment for the medical community to improve targeting of PSA screening in patients, reduce over-testing and improve processes of patient education on the risks of overtreatment from PSA screening.” See also the June 2012 edition of Prostate Cancer Advances, “PSA: Better Patient Education.”
Finally, targeted screening using specific biomarkers is urgently needed to identify and differentiate between aggressive cancers requiring treatment and those best followed by “active surveillance”. Examples of such biomarkers include a urine test to identify abnormally high levels of genetic RNA made from the PCA3 gene in prostate cancer cells. This urine test commercialized by Gen-Probe and known as PROGENSA PCA3, was approved by the Food and Drug Administration (FDA) in February of this year. A National Cancer Institute (NCI) study examined the predictive value of using PROGENSA PCA3 to detect prostate cancer. A positive PCA3 test predicted a positive biopsy of 80 percent of the time at initial biopsy; and, for men undergoing repeat biopsies, a negative urine test predicted a negative biopsy 88 percent of the time.
Still another example of a potential biomarker being studied at Cornell, MIT and Harvard Universities is the identification of mutations in a gene called SPOP. Such genetic alterations may be unique to early stage prostate cancer. These are just two examples of potential targeted screens which hopefully will one day replace the PSA test to provide more precise information to guide physicians and their patients in their diagnoses and possible treatments if necessary.
New Developments in Prostate Cancer Biomarkers.
Two articles discussing the development of new genetic tests which could potentially be used to detect and determine aggressive prostate cancers were published in the May 2nd and May 15th issues of the Zerohour Newsletter of the Project to End Prostate Cancer.
The biggest problem facing men who have been diagnosed with prostate cancer is to determine whether the cancer is potentially aggressive and therefore requires treatment or whether it can be subject to “active surveillance”. PSA values alone will not answer this question. However, genetic changes or biomarkers are being actively sought by researchers to help determine the aggressive nature of the cancer. Three such genes are named ERG, ETV1 and PTEN. Researchers at Stanford University and Abbott Molecular are working to develop a molecular assay to detect rearrangements of the ERG and ETV1 genes and measure loss of the PTEN gene. A study published in the British Journal of Cancer evaluated 308 prostate cancer patients who were treated conservatively. “Those who did not show abnormal ERG/ETV1 genetic changes with no PTEN gene loss had excellent prognosis, as evidenced by an 85 percent survival rate after 11 years. Men who showed PTEN gene loss in the absence of the gene rearrangements had a poor survival rate of 13.7 percent. The study showed the promise of the new biomarkers to identify patients who would benefit most from intensive therapies.”
In another study, researchers at the Mayo Clinic have found that changes to the “on-off” switches of genes occur early in the development of prostate cancer and could be used as biomarkers to detect the disease months or even years earlier than current approaches. “These biomarkers — known as DNA methylation profiles — also can predict if the cancer is going to recur and if that recurrence will remain localized to the prostate or, instead, spread to other organs. The study, published in the journal Clinical Cancer Research, is the first to evaluate the methylation changes that occur across the entire human genome in prostate cancer. The discovery could someday help physicians diagnose prostate cancer earlier and make more effective treatment decisions to improve cure rates and reduce deaths. It also points to the development of new drugs that reverse the DNA methylation changes, turning the “off” switch back “on” and returning the genetic code to its normal, noncancerous state.”
Anxiety-How to Win Our Biggest Battle.
I recently met with a well-known urologist whose research focuses on the use of our immune system to combat prostate cancer. In our conversation, I was able to share my own prostate cancer history and current status. He echoed the comment that had been stated by my oncologist and assured me that since there were so many current and future treatment options now available, I would more than likely outlive my own prostate cancer and die of another cause. The urologist went on to state that the biggest problem facing his prostate cancer patients is their own angst. I could certainly echo his sentiment.
In my own case, I had been diagnosed with prostate cancer in 1995. Shortly thereafter, I underwent a successful radical prostatectomy at Johns Hopkins. My cancer was completely localized, had not spread and my Gleason score was an average value of 3+3 or 6. I was an ideal candidate for a “cure”. But the cancer (PSA) returned 7-8 years later and was not completely eradicated by radiation therapy. My PSA doubling time had become 2-3 months, indicating an aggressive cancer. A former colleague of mine had published a paper in a peer-reviewed journal in which he concluded that patients like myself with such a short doubling time could expect an average 5-year survival period. The period of 1995-2004 was filled with lessons I had learned both medically and especially spiritually but it was interspersed with periods of high personal anxiety as recounted in this website (see My Story and Lessons Learned). I am currently asymptomatic and undergoing intermittent therapy. I have continued to pray that God would not allow this disease to take my life and He seems to be reinforcing His answer to me through His word and the predictions of two well-known oncology and urology physicians. God had allowed me to experience this cancer scenario for other reasons, such as that He would be glorified through my experiences and that other men might be encouraged.
I have learned that anxiety can become a bondage and is an individual choice. The apostle Paul states in Philippians 4:6-7 that Christians are to “be anxious for nothing, but in everything by prayer and supplication” (asking), “with thanksgiving, let (y)our requests be made known to God. And the peace of God which surpasses all understanding, will guard (y)our hearts and minds in Christ Jesus.” Worry indicates a lack of trust. I have often worried about the possibility of receiving negative results or news. When the actual results were known, they were never as bad as I had imagined and many times they were very positive. Negative results can serve as tests of our faith. God was showing me that I had a lack of trust and that my own anxiety was a faith battle which indicated that my own faith needed to be re-directed and strengthened. I am to release my anxiety to God and admit that I cannot handle the situation in my own strength. I simply need to trust that God will answer in His way and His time according to His purpose (see Jeremiah 29:11). This will also validate my own personal relationship with God and that it is not simply intellectual knowledge and mis-placed faith. When we enter into a personal relationship with God, every promise in His Word (such as that above) becomes applicable to us.
Jesus Himself is our greatest example of how to handle anxiety. It is always encouraging to realize that He is both divine and human, and as such can associate with our own feelings. This is best exemplified by Christ’s experience in the Garden of Gethsemane prior to His crucifixion. He had been betrayed and denied by His own friends and disciples. Yet He cast His burden on His Father. First, like us, He prayed that His potential suffering be removed. In Matthew 26:39 He prays for deliverance, “O My Father, if it is possible, let this cup pass from Me.” I am sure any prostate cancer patient can relate to this statement. Then Jesus expresses acceptance stating “nevertheless, not as I will, but as You will.” In verse 42 He prays “O My Father, if this cup cannot pass away from Me unless I drink it, Your will be done.” The fact remains that we who have been diagnosed with prostate cancer must accept its medical reality. But there is better news. Jesus’ third prayer was a desire that God’s grace be seen in Him and that His Father would be glorified. In John 12:27-28, Jesus prays “But for this purpose, I came to this hour. Father, glorify Your name.” As a direct result of our personal relationship with God, we too can cast our burdens and anxiety on the Lord and help others to do so. For me, I often visualize packaging my anxiety in a container and laying it at Jesus’ feet or at the cross. May our deepest desire be that God’s grace and goodness would be seen in us and that He would be glorified in our individual scenarios and outcomes.
A Vitamin D – Prostate Cancer Connection and Other News.
There has been much discussion concerning the role of blood vitamin D levels and its metabolism and their relationship to prostate cancer. A study examining this relationship published in the April 12th issue of the Journal of the National Cancer Institute found that men with the highest plasma levels of vitamin D “were 57% less likely to develop a lethal form of the disease.” Plasma vitamin D levels and common variation among several vitamin D-related genes associated with its metabolism were associated with lethal prostate cancer risk, suggesting that vitamin D is relevant for lethal prostate cancer. However, vitamin D levels did not affect the chances of developing prostate cancer. It should be noted that vitamin D levels were determined by the 25-hydroxyvitamin D assay and not the 1,25-dihydroxy assay. One can attain sufficient vitamin D levels from foods, D3 supplements of varying strengths (units) as well as from calcium citrate or calcium carbonate supplements which also contain vitamin D. It is strongly recommended that the amount (units) of vitamin D required to maintain an optimal blood level should be determined in consultation with a physician as highly excessive amounts may be harmful. Optimal serum levels of vitamin D are 20-50 ng/mL in the USA according to some sources while others recommend 50-80 ng/mL. (International levels are 50-125 nMol/L.) A summary of this research appeared in the April 27th, 2012 issue of the Prostate Cancer Foundation NewsPulse. In addition to this study, this issue of NewsPulse also contained articles dealing with High-Intensity Focused Ultrasound (HIFU) treatments and proton beam radiation therapy.
The April 3rd, 2012 issue of ZeroHour from the Project to End Prostate Cancer contained two articles of specific interest. One described a study concluding that oxygen levels measured in tumors might be used as a good predictor of prostate cancer recurrence. The other discussed a new zirconium radiotracer (89Zr-5A10) designed specifically to target free PSA (a better biomarker of prostate cancer) as opposed to serum PSA. This radiotracer can be used in conjuction with positron emission tomography (PET) to identify metastatic bone lesions in a more specific manner than traditional bone scans.
The April 14th, 2012 issue of the Prostate Cancer Research Institute (PCRI) Weekly contained information about availability and enrollment in Phase III clinical studies of alpharadin (radium-223 chloride) in hormone-refractory patients with symptomatic bone metastases. Alpharadin uses alpha-particle radiation from radium-223 to kill cancer cells by specifically targeting bone metastases by virtue of its property as a calcium mimic. It is being developed by a Norwegian company, Algeta ASA in collaboration with Bayer.
HisProstateCancer.com, a Website for Wives and Family Members of Men With Prostate Cancer.
Recently I was contacted by a woman whose husband had been diagnosed with prostate cancer at the age of 49. He underwent a radical prostatectomy and subsequent radiation therapy. Their experience led to the generation of the website, HisProstateCancer.com with its specific focus to wives, partners and family members of prostate cancer patients. I recommend this site for your review.
A New Urine-Based PC Assay, Clinical Trials Providing Earlier Access to New Therapies and Other News from February-March, 2012.
It has been a month since I last updated this website and there have been significant news items which are summarized below.
1) FDA Approves a PCA3 Urine-Based Assay for Prostate Cancer that Could Reduce Unnecessary Prostate Biopsies. On February 15th, 2012, the U.S. Food and Drug Administration (FDA) approved a urine-based molecular diagnostic test that aids clinical decision-making for repeat prostate biopsies in men who have had a previous negative biopsy. The test, developed by Gen-Probe, is called PROGENSA PCA3 (Prostate Cancer Antigen 3) assay. It tests for levels of PCA3 in the urine of men immediately after a digital rectal examination. PCA3 is produced by a gene that is normally expressed only in human prostate tissue and is highly expressed in 95% of all prostate cancer. Thus the product of this gene is excreted in the urine of men with prostate abnormalities. The current prostate-specific antigen (PSA) screening test for prostate cancer is prostate-specific but not highly cancer-specific which is the case for PCA3 testing which has better positive and negative predictive values. Therefore, this test will aid faster and more efficient diagnosis of prostate cancer thereby minimizing additional repeat biopsies and their undesirable side effects including infections. Additional details are available from Gen-Probe, in the March 20th, 2012 issue of the ZeroHour Newsletter and the February 27th, 2012 issue of the Prostate Cancer Foundation NewsPulse.
2) Patients Being Recruited for Clinical Trials Involving Provenge, Zytiga and/or Hormonal Therapy. During the last 1-2 years, several new therapeutic agents have been approved by the FDA for treatment of men with metastatic prostate cancer or who have had prior chemotherapy. The strategy now seems to be the application of these agents in men with earlier stage prostate cancer. To determine the effectiveness of such strategies, two clinical trials are described involving Sipuleucel-T (Provenge), abiraterone acetate (Zytiga) and androgen deprivation (hormonal) therapy (ADT). The first is entitled “Concurrent Versus Sequential Treatment with Sipuleucel-T (Provenge) and Abiraterone (Zytiga) in Men With Metastatic, Castration-Resistant Prostate Cancer (mCRPC).” This trial may provide earlier access to Zytiga for men who have not had chemotherapy. It is currently recruiting patients in the following locations: Denver, CO; Seattle, WA and Virginia Beach, VA.
The second trial entitled “Sequencing of Sipuleucel-T (Provenge) and ADT in Men with Non-Metastatic Prostate Cancer”, may provide earlier access to Provenge for men who have recurrent but non-metastatic prostate cancer. The trial is designed to determine whether ADT (hormonal therapy) started before or after sipuleucel-T leads to superior augmentation of immune response to sipuleucel-T. This trial is currently recruiting patients in the following states: Alabama, California, Colorado, Maryland (Johns Hopkins), New York, South Carolina, Texas and Washington. For details of both trials, see the Prostate Cancer Research Institute (PCRI) Weekly (Volume 2, Issue 2) of March 2nd and 8th, 2012.
3) Oligometastatic Prostate Cancer; an Intermediate Stage? The February 27th, 2012 issue of the Prostate Cancer Research Institute (PCRI) Insights contained several articles of interest including an update on brachytherapy and especially an article on an intermediate stage of prostate cancer termed oligometastatic prostate cancer. The authors, including Dr. Charles “Snuffy” Myers, outline the concept of this intermediate stage wherein cancer has spread outside the prostate gland but is not widespread. Pros and cons of various imaging techniques used to identify such metastatic sites are described. These sites are not always easily observed by CT or MRI scans. The authors’ focus is not merely on bone metastases but lymph node metastases as well. Identified metastatic sites are then subjected to carefully focused radiation therapy such as provided by advanced versions of Intensity Modulated Radiation (IMRT) such as Image-Guide (IG) IMRT and Dynamic Adaptive Radiotherapy (DART 4D) therapy.
4) Continued Development of OncoGenex’s OGX-427, a New Type of Anticancer Therapy. OGX-427 is a second-generation antisense drug designed to reduce the production of heat shock protein 27 (Hsp 27), a protein that regulates multiple cell mechanisms that cancers use to survive. Hsp 27 inhibits apoptosis (cell death), is found at high level in many human tumors especially hormone-resistant prostate cancer and is implicated in cancer progression and treatment resistance. Hsp 27 can also be induced by cell stress through chemotherapy, radiation or hormonal therapy. When co-administered with prednisone, OGX-427 demonstrated promising results in a Phase II clinical trial versus prednisone alone. A new Phase II trial of OGX-427 in men with minimally symptomatic or asymptomatic advanced prostate cancer who have not yet received chemotherapy has recently been announced. This Phase II trial will measure disease progression at 12 weeks, PSA levels, time to progression by PSA or measurable disease, numbers of circulating tumor cells (CTCs) and other endpoints. For additional details, see the Prostate Cancer Foundation NewsLetter, February 27th, 2012 and the OncoGenex website.
5) Custirsen (OGX-011) to be Further Evaluated in Phase III Trials. OncoGenex Pharmaceuticals and its partner Teva Pharmaceuticals plan to start a new Phase III trial for custirsen in combination with Sanofi’s approved taxane chemotherapy drug, Jevtana with the goal of improving survival in prostate cancer patients. A separate trial called Synergy, which aims to test custirsen in combination with chemotherapy in hormone-resistant prostate cancer patients, is boosting its patient enrollment. For further information see the March 20th, 2012 issue of the ZeroHour NewsLetter.
6) Alpharadin Update. The February 27th, 2012 issue of the Prostate Cancer Foundation NewsPulse had several articles of interest. One was an update on the therapeutic effects of the alpha-particle emitting Alpharadin (Radium-223) which is targeted to bone metastases and potent, localized, tumor cell-killing activity within a 10-cell radius. It’s half-life of 11.4 days seems to make it an ideal candidate for cancer therapy.
Positive Treatment Developments from Three Sources.
At the Feb. 2nd-4th, 2012 meeting of the American Society of Clinical Oncology (ASCO), positive results were presented for two different prostate cancer treatments both currently under late stage Phase III clinical development. The positive results led to the studies being stopped earlier than anticipated. These two drugs, radium-223 chloride (Alpharadin) and MDV3100 were both found to increase survival in metastatic, hormone-refractory prostate cancer patients and control the growth of bone metastases. Radium-223 chloride demonstrated improved survival and delayed cancer-related bone problems in men with advanced, spreading tumors. It delivers bursts of about four one thousandths of an inch of localized alpha radiation to the bone, thereby targeting the tumor. In addition, the average time to the first bone-break, fracture or need for radiation or surgery was significantly delayed among men treated with the new drug. The U.S. Food and Drug Administration (FDA) said it will fast track both Alpharadin and MDV3100 in its approval process for treatment in men with metastatic, hormone-resistant prostate cancer.
The second drug, MDV3100, increased survival by close to five months among men with advanced prostate cancer. This drug works by two routes. First it prevents testosterone from binding to receptors on cancer cells which require these male sex hormones in order to survive and grow. Secondly, MDV3100 prevents the production of proteins within the cell that induce tumor growth.
The next step for clinical researchers is to determine the best combination and sequence of administration of these two drugs in order to hopefully demonstrate their synergistic benefit which researchers believe is very plausible.
These positive reports were all recently independently published in: a) the ZeroHour Newsletter, Issue 26, Feb. 7th, 2012; b) the Feb. 7th, 2012 issue of the National Cancer Institute (NCI) Cancer Bulletin; and c) the February 9th on-line issue of the Prostate Cancer Research Institute (PCRI) Weekly (Volume 1, Issue 8). Additional highlights of the 2012 Genitourinary Cancers Symposium held at the Feb. ASCO meeting are also presented in the PCRI Weekly.
The same issue of the Feb. 7th NCI Cancer Bulletin also contained an analysis of the potential benefits and harms of three types of radiation therapy, a more recent proton therapy, brachytherapy and surgery for prostate cancer. Men considering any of these forms of therapy are urged to read this report and discuss it with their respective physicians.
PSA Screening Updates – Use of Nomograms.
As you may have heard, in 2011, the U.S. Preventative Services Task Force (USPSTF) issued a controversial recommendation to no longer recommend prostate-specific antigen (PSA) screening for healthy men under the age of 75. The USPSTF’s recommendations often guide physicians in their decisions as well as impact what tests Medicare and private insurers will pay for. This recommendation evoked considerable response from the medical community.
The Johns Hopkins Hospital is consistently rated as the nation’s #1 urology department according to the annual survey published in U.S. News and World Report. They published a response in the Jan. 3rd, 2012 issue of their Health Alerts entitled “Should You Have a PSA Screening Test? Johns Hopkins Responds to Recent USPSTF Recommendations.” I encourage you to read the linked article. They concluded that targeted PSA screening focused on men with greater risk and active surveillance for those not requiring immediate treatment could shift the benefit / risk ratio toward greater benefit. Screening should not be discontinued but focused on reducing harm.
It is agreed that it would be desirable to limit the number of unnecessary prostate biopsies and their resulting side effects. To this end, the Johns Hopkins Health Alerts (December 22, 2011) discussed the use of nomograms to address problems with using specific PSA values to ascertain the need for a biopsy. A nomogram considers multiple weighted factors to calculate risk of having biopsy-detectable prostate cancer. These factors include race, age, PSA level, family history, digital rectal exams (DRE) and results of previous biopsies and whether one has previously taken finasteride (Proscar).
Another important factor which could be used to identify candidates for biopsies is PSA density (PSAD). In a recent article published Dec. 12, 2011 in Medical News Today (a recommended source of prostate cancer information), Dr. Martin Sanda of Harvard Medical School wrote that PSA screening could be improved to identify only aggressive cancer requiring treatment by adjusting various factors like prostate size (volume, density, PSAD), obesity and family history. In my own case in 1995, my PSA values at the time of cancer detection averaged around 4 ng/ml. I had undergone a routine biopsy in 1994 which revealed no cancer but concluded that my prostate gland itself was not enlarged. I therefore reasoned that my smaller prostate gland seemed to be producing a more significant amount of PSA (4.0) than it might under normal conditions. Following up with a second biopsy in October, 1995, the presence of cancer was revealed. Therefore I was using the concept of “PSA density” (PSAD) without knowing about it medically. In his article, Dr. Sanda also recommended nomograms to predict aggressive cancers and identify candidates for biopsies. The use of two specific urine genetic biomarkers, TMPRSS2:ERG and PCA3, (see Sept.21, 2011 post) was also mentioned in the article entitled “PSA Testing Combined with Other Relevant Patient Data Can Reduce Unnecessary Prostate Biopsies.” The article was also cited in the January 10th, 2012 issue of the ZeroHour Newsletter (from Zero-The Project to End Prostate Cancer).
Lastly, WebMD is an illustrated internet resource that covers many medical issues. One can however choose those areas of specific interest such as prostate cancer. On Jan. 24th, 2012, the WebMD-Cancer published an illustrated introductory primer dealing with prostate cancer. WebMD-prostate cancer should be added to the list of medical resources.