Galeterone is a Copy Cat of Zytiga

Galeterone (TOK 001) is a new drug for prostate cancer that is undergoing clinical trials. This is one of a number of 17-heteroaryl substituted analogues of abiraterone (Zytiga). Galeterone has a 17-benzimidazole group in place of the 17-3-pyridyl group found in Abiraterone. Galeterone is therefore a copy cat version of Zytiga and should have the same clinical benefits.

Lower Dose Zytiga Makes Economic Sense

In the UK the agency NICE has rejected the use of Abiraterone in the National Health Service (NHS) based on cost grounds. This is based on receiving a dose of 4 tablets daily without food. However recent research at the University of Chicago show that the drug uptake is increased 5 fold if taken after food and so a dosage of only 1 capsule daily is needed if taken with food. This would cut the monthly cost from £3000 per month to only £750 per month, resulting in a considerable cost saving.

In an utterly unsurprising announcement from the UK, the National Institute for Clincial Excellence (NICE) has issued draft guidance in which it refuses to cover the proposed cost of abiraterone actetate.
This draft guidance looks suspiciously like the first round in a negotiating process with the manufacturer of abiraterone acetate. Why? Because Andrew Dillon, NICE’s chief executive has indicated that the draft ruling could be reconsidered and that the manufacturer might want “to further reduce the acquisition cost to the NHS of the drug by proposing a revised patient access scheme.”
According to the manufacturer, the proposed cost of abiraterone acetate in the UK was £2,930 (US$4,638) for a 30-day supply. The company has already stated that it would “be actively participating in this consultation as we strive for a positive outcome for patients.”
Dillon is also quoted at saying that abiraterone acetate ”could potentially extend life by more than 3 months, compared with placebo,” but that NICE’s advisory committee “did not feel [it] provided enough benefit to patients to justify the price the NHS is being asked to pay, even with the discount that the manufacturer has offered.”
The agency also determined that the treatment did not meet its criteria to be considered under special arrangements for drugs treating people at the end of their life, as “the population for which it is licensed cannot be considered to be small.”
One of the upsides of nationalized health care systems is that health care is provided to all. One of the downsides is that every new drug and treatment may not be available through such a system until this type of financial negotiation can be completed, which just takes time.
Abiraterone acetate was approved in Europe last September as a treatment for men with metastatic castration-resistant prostate cancer (mCRPC) whose disease has progressed on or after receiving docetaxel-based chemotherapy. It must be given in combination with prednisone or prednisolone.

6 Responses

1. Dr Potter, on February 2, 2012 at 11:09 am said:

   The high cost of abiraterone at £3,000 per month is based on the high dosage of 4 tablets per day. This high dosage is only needed for the first month and can be decreased to 1 tablet per day, giving a long-term cost of only £750 per month. The same scientists have also developed salvestrol platinum which has been shown to be powerful against all forms of cancer, including prostate cancer, and is available in the UK for £60 per month.
   
2. Sitemaster, on February 2, 2012 at 11:23 am said:

   Dear Dr. Potter:
   Are you able to provide references for the clinical use of abiraterone acetate at 750 mg/d and for the use of salvestrol platinum in the management of prostate cancer? I am not familiar with such data.
   
3. Terry Herbert, on February 2, 2012 at 3:30 pm said:

   I found it interesting that a circular looking for men to support a petition to persuade NICE to reverse the decision contains this statement to justify the cost:
   The potential to increase life by years. Not just 4 months. On the 9 month trial, nobody on the drug died. Men on the placebo arm of the trial started to die after 5 months. Hence 4 months of extra life.
   I thought the median survival was about 14 months and understood that to mean that half the men died before that period?
   
4. Sitemaster, on February 2, 2012 at 4:53 pm said:

   Terry:
   Alas, some people have minimal appreciation of the science of clinical trials!
   
5. George Kenneth Berger, on February 2, 2012 at 5:40 pm said:

   An influential, intellectual, and politically important British newspaper, The Guardian, published an article entitled “Cancer drug ‘too expensive for NHS’” about this issue online today. … Well worth reading for its detail and information on the initial reactions.
   
6. Dr Potter, on February 4, 2012 at 7:12 am said:

   Abiraterone is an exceedingly potent drug, active at the nanomolar level. The high dose of 4 tablets (1 gram) per day was arrived at from the Phase 1 clinical study, which showed this to be the maximum effective dose. The minimum effective dose was 250 mg, which is equivalent to 1 tablet per day. The high dose of 1 gram per day is needed to adjust the body to total androgen deprivation. After a month the LHRH signals have subsided and so a lower maintenance dose can be given. This and other aspects are being investigated in over 34 different ongoing clinical trials on abiraterone.
   The use of Salvestrol Platinum in the managment of prostate cancer has been published in a series of case studies in the Journal of Orthomolecular Medicine which can be found by searching on Salvestrol Case Studies. An example of one of these case studies is added below:
   Case #3. Prostate Cancer
   A 74-year-old gentleman was diagnosed with prostate cancer. Subsequently this gentleman spoke with his cousin, a university lecturer, who told him that one of his students was diagnosed with a terminal brain cancer who had recovered after taking Salvestrols. He decided to begin a course of Salvestrol supplementation taking two (350 point) Salvestrol Shield capsules per day. Six months after receiving his diagnosis his PSA level had dropped from 11 to below 1 ng/mL. The patient moved to another country which necessitated a change of doctors. At this point the patient switched Salvestrol products and began taking one (2,000 point) Salvestrol Platinum capsule three times per day after meals, to give a total supplementation of 6000 points per day. Twelve months after receiving his diagnosis his PSA level had dropped to 0.2 ng/mL. The new doctor continued with the PSA monitoring and upon receiving a subsequent PSA test result the physician said that the PSA level received was as low as it could be and asked if the patient was sure that he had not had surgery. Given the physician’s surprise that such a result could be achieved the patient confessed to taking Salvestrols. The physician then stated that he had other patients he would like to start on Salvestrols. This patient continues to receive PSA test results at the 0.2 ng/ml level and has continues to take one (350 point) Salvestrol Shield capsule per day as a preventive measure, and has now embarked on a fitness program and change in diet.

Can Zytiga be Used at Just 1 Tablet Daily ?

Long-term use of abiraterone acetate at 250 mg/d: is this really viable?

It has been suggested that, after an initial “loading dose” for a period of time, abiraterone acetate could potentially be used to treat metastatic, castration-resistant prostate cancer (mCRPC) at a much lower daily maintenance dose than that currently approved.
In two messages left on this site (on February 2 and on February 4, 2012), Prof. Gerry Potter (one of the original developers of abiraterone acetate) has stated his opinion that, after initial treatment with a “loading dose” of abiraterone acetate at 1,000 mg/d for a period of 1 month, many patients could potentially be managed with a much lower daily (maintenance) dose of this agent at just 250 mg/d.
We have the greatest respect for Dr. Potter as a medicinal chemist, and we feel very sure that his opinion is based on data available to him that gives him confidence in this clinical strategy … but, we feel it is important to note the following:

• We know of no large-scale clinical trial that has ever tested this concept in men with metastatic prostate cancer.
• No completed, ongoing, or proposed trial of abiraterone acetate currently listed on the ClinicalTrials.gov web site has tested or appears to be designed to test this concept.
• The currently approved dose of abiraterone acetate (in the treatment of men with mCRPC who have previously received at least one cycle of docetaxel-based chemotherapy, in both the USA and Europe) is four 250 mg tablets of abiraterone acetate once daily for a total daily dose of 1,000 mg/d — in combination with prednisone at a dose of 5 mg twice daily.
• Dr. Potter is not a physician, and he does not treat patients with prostate cancer. He is a medicinal chemist with considerable experience in the development of therapeutic agents for the treatment of cancer and other disorders.

Having carefully stated these facts, we have to say that the concept presented by Dr. Potter is intriguing. Abiraterone acetate at a dose of 250 mg/d was tested clinically in a very small number of patients in Phase I trials, and data on the pharmacokinetics of this dose level were reported by Ryan et al. in 2010. It was the lowest dose of the drug used in these early stage trials and may well have significant clinical activity after an appropriate loading dose.
However, we really have no idea whether such a clinical strategy would have the same level of effectiveness as the currently recommended and approved dose of abiraterone. It also seems unlikely that the manufacturer of abiraterone would be interested in testing such a concept. This does not, of course, mean that others could not implement a clinical trial to test the concept; after all, maintenance with a lower dose of abiraterone might impact any cumulative side effects of this agent and would most certainly impact the cost of treatment with this drug over time. One also has to ask whether use of such a maintenance dose level of abiraterone acetate could be associated with a reduction in the daily dose of predisone (which would reduce the impact of the side effects of corticosteroid therapy as well).
We wish to be extremely clear that The “New” Prostate Cancer InfoLink is not recommending (and is in no position to recommend) the use of abiraterone acetate at anything other than the dose approved by regulatory authorities in the USA and Europe. We are merely responding to the suggestion made previously by Prof. Potter.

10 Responses

1. gerald Chodak, on February 6, 2012 at 10:54 am said:

   Your comments are perfect! Any doctor prescribing a lower dose of the drug would be subject to liability issues in the event a patient did not do well, so it is highly unlikely that the lower dose will ever be an issue. One wonders, however, whether testing a lower dose in men with a rising PSA without metastases would be worthwhile.
   
2. JimWaldenfels, on February 6, 2012 at 4:20 pm said:

   HOW ABOUT BIOMARKERS TO MONITOR CONTINUED FAVORABLE RESPONSE AT LOWER DOSE, PRESCRIBED “OFF-LABEL”?
   In the meantime, I hope that some physicians, at the request of patients, will make wise and prudent use of off-label prescription procedures to try the lower dose proposed by Prof. Potter, with careful monitoring of biomarkers. I suspect that is already happening. If it does happen, I'm hopeful that some of those doctors will carefully track results and share them via published papers.
   It would be nice if we patients, scientists, and physicians could wait until that day comes when all the science lines up perfectly and clear guidelines are published. However, patients with challenging cases, like me and the mCRPC patients, often lack the luxury of time!
   
3. Charles (Chuck) Maack, on February 6, 2012 at 9:09 pm said:

   No particular comment other than both Sitemaster’s and Jim’s comments are well explained. With the cost of abiraterone/Zytiga at four 250 mg tablets daily somewhat prohibitive and this protocol apparently lasting somewhere between six and eight weeks before ending and then monitoring continuing results, the subsequent prescribing of Zytiga/abiraterone at a lower dose and monitored for continued effectiveness appears to be to be a reasonable “maintenance” protocol.
   
4. Tom, on February 6, 2012 at 10:45 pm said:

   I think oncologists are more flexible with the abiraterone dose than many might realize. My dad is prescribed 500 mg a day WITH food as opposed to 1,000 mg a day in a fasting state. The rational is taking the medication with food will induce more absorption of the drug; at least equivalent as the dose tested in the clinical trial in a fasting state. Its common sense people, and this drug is expensive. For half the price, his PSA has dropped 80% after 2 months of treatment.
   
5. Ralph Valle, on February 6, 2012 at 11:01 pm said:

   For what is worth … I know a patient that was on the 1000 mg dose for 2 months. He had a PSA reduction response of 95% (10.5 to 0.5 ng/ml). At that point he reduced the dose (on his own) to 500 mg. Now with PSA trending down (0.2) he is contemplating going to 250 mg/day. This patient has used ketoconazole before and was able to titrate the dose to fit his need. Now he is doing the same while saving mega $$$s. This fits with Dr. Potter’s advice.
   
6. Sitemaster, on February 6, 2012 at 11:05 pm said:

   Dear Tom:
   There is a reason that it is recommended that abiraterone acetate not be taken with food. I quote from the instructions to patients:
   “Take ZYTIGA® on an empty stomach. Do not take ZYTIGA® with food. Taking ZYTIGA® with food may cause more of the medicine to be absorbed by the body than is needed and this may cause side effects.”
   It is certainly possible that by cutting the dose to 500 mg/d one may be able to avoid the risk of excessive side effects, but there are no data to support such a clinical strategy, and there are therefore unknown risks associated with this strategy. “Common sense” may have great value under appropriate circumstances, but not everything that appears to make “common sense” is necessarily sensible in retrospect.
   Over the years, clinicians have done all sorts of things that appeared at the time (at least to the physicians concerned) to make “common sense” (e.g., “cupping,” deliberate bleeding of patients, treatment with arsenic and mercury, I could go on for hours). There are a whole host of such “common sense” treatments that we would consider to be horrifically bad medical practice today.
   Obviously I am pleased to hear that this strategy is working for your father to date … but please beware of generalizations.
   
7. Dr Potter, on February 10, 2012 at 6:09 am said:

   This discussion has raised another question and that is, “Can abiraterone be taken with food?”
   This is a somewhat controversial area, so I will give my opinion as a pharmacologist rather than as a doctor.
   The manufacturer’s prescribing instructions for abiraterone (see section 5.4, Food Effect) state clearly that it should not be taken with food:
   “ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone C_max and AUC_0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.”
   This is because the clinical data for this disease indication has been conducted at a dose of 1 g daily taken without food.
   It is worth re-stating the fact that abiraterone is an exceedingly potent drug, so that it has always surprised me when such high doses (1 gram) of abiraterone acetate are used. Abiraterone is five times more potent than letrozole (Femera), an aromatase inhibitor used to treat breast cancer, which is taken at a daily dose of 20 mg. So why isn’t abiraterone taken at a dose of 20 mg. The main reason is the poor uptake of abiraterone acetate in the un-fed state. Abiraterone acetate has been specially formulated as the acetate to help increase intestinal absorption and bioavailability through absorption by digestion. Without food digestion, there is poor absorption. The main reason for such high doses is therefore due to the very poor absorption of abiraterone acetate by the intestine in the un-fed state. Given on an empty stomach, only about 5% of abiraterone is absorbed by the intestine, so for a 1 g (1000 mg) dose only about 50 mg is absorbed and the remaining 950 mg is excreted. What a waste of drug when 95% is excreted. It would make far better sense if the absorption of the drug can be increased somehow, as is found when the drug is taken with food. Abiraterone was designed as an orally active drug, and as such was designed to be absorbed with food. When abiraterone is taken with food, the absorption increases dramatically — by 10-fold. The area under the curve (AUC) exposure is a measure of the volume of the drug absorbed into the bloodstream and this increased 10-fold when abiraterone was administered with a meal. So it is important to realise that the concentration of abiraterone in the body increases 10-fold when taken with food. In this way a 100 mg dose will deliver the same amount of drug as a 1000 mg dose without food. This means a dose as low as 100 mg could be taken with food to deliver the same pharmacological effect as 1000 mg without food.
   Since it appears that some clinicians are already administering abiraterone with food, it should be borne in mind that a single tablet dose of 250 mg taken with food will deliver 2.5 times more drug than 4 tablets taken without food.
   
8. Sitemaster, on February 10, 2012 at 7:55 am said:

   Thanks Dr. Potter. This is very helpful for people.
   
9. Frank Flynn, on February 10, 2012 at 5:10 pm said:

   I have been on a Zytiga/prednisone regime for almost 2 months now. The treatment seems to be having little or no effect and my PSA continues to rise. Admittedly I have a very aggressive PCa (Gleason 10, Stage IV mCRPC).
   I would be very interested in trying smaller doses, say 250 mg taken with food and will approach my oncologist about this at our next meeting. I have little hope that he will go along with this because of the general reluctance of physicians to expose themselves to litigation. So if he opposes the idea, I believe I will experiment on my own with reduced dosage plus food. I believe I have very little to lose by doing so. The advanced state of my disease leaves me very few options to explore. Thank you Dr. Potter for your information. That and some of the testimony of readers will help me make a final decision.

Zytiga Reduces Fatigue in Men with Prostate Cancer

Abiraterone Acetate treatment reduces fatigue in men with mCRPC

According to a retrospective analysis of data from a randomized, double-blind, Phase III clinical trial, abiraterone acetate (Zytiga™) can significantly lower levels of fatigue in men with metastatic, castration-resistant prostate cancer (as well as extending survival).
These data were presented today at the European Multidisciplinary Cancer Congress by Dr. Cora Sternberg and colleagues. They are based on a re-analysis of information collected as part of the original Phase III clinical trial that led to the approval of abiraterone acetate for treatment of men with mCRPC earlier this year.
Dr. Sternberg is quoted as stating that:

One of the most distressing issues these metastatic castration-resistant prostate cancer patients face during hormone treatment is extreme fatigue. Our results show that zytiga therapy has the potential to reduce cancer-related fatigue in this patient population, in addition to the previously demonstrated survival benefit

Cabozantinib Zytiga Combo

Cabozantinib and Zytiga make an exciting combination of drugs and expectations are high with the combined use of these drugs. Zytiga is already licensed for advanced metastatic prostate cancer and has to date shown encouraging activity in late stage disease. Cabozantinib targets the metastatic cancer and has been shown to decrease bone metastasis in Phase 2 trials. There is also a decrease in bone pain in patients receiving Cabozantinib. This drug targets the tyrosine kinase enzymes VEGFR and MET that are involved in angiogenesis and metastasis. A new trial has been announced that is to investigate the use of both these drugs in combination in a Phase 1 study. Since both these drugs have already been safely tested in Phase 2 and Phase 3 trials then the combination makes a worthwhile study.

Rationale for Combination Approach

Clinical and preclinical evidence suggest that inhibition of androgen receptor signaling (a consequence of treatment with the androgen synthesis inhibitor Zytiga) results in upregulation of a resistance mechanism mediated by MET signaling, which may contribute to the survival and invasiveness of prostate cancer cells. Cabozantinib is a potent inhibitor of MET, and may therefore enhance the activity of abiraterone by blocking this putative resistance mechanism. Additionally, the high level of activity that cabozantinib has demonstrated against both soft tissue and bone lesions in men with CRPC may complement the clinical activity of Zytiga.

Can Zytiga be Taken at a Lower Dose ?

Take Two of These…and a Sandwich

Posted at 8:27 am CT on April 18, 2012

By John Easton
“Take medication on an empty stomach.” Patients dread seeing this warning on their pill bottles, knowing that it often means skipped meals and hungry rumbles in the hours before and after taking their medicine. The rationale for the empty stomach is to avoid the unpredictable effects of food on drug metabolism — depending on what you’ve eaten, different amounts of the medication can be absorbed into the bloodstream. But a new clinical trial at the University of Chicago Medicine is testing whether just the right mixture of food and drug could be more convenient for patients while saving a whole lot of money.

Abiraterone (trade named Zytiga), is a drug prescribed to men with castration-resistant prostate cancer. It also is more sensitive to food’s effects than any other marketed drug that is labeled to be taken on an empty stomach. Five times as much of the drug is taken up with a low-fat meal as on an empty stomach, and up to 10 times as much with a high-fat meal. Yet patients are told not to eat for two hours before and for one hour after taking their pills. As a result, taking Zytiga as directed means the amount of the drug absorbed by the body to fight cancer is decreased by 80 to 90 percent.

“This clinical trial is designed to assess the risks and benefits of taking this effective but costly drug with food,” said Russell Szmulewitz, assistant professor of medicine at the University of Chicago Medicine and director of the study. “Taking one pill with a meal, rather than four pills on a empty stomach, is much more convenient for patients, so it may improve compliance. It would also reduce the cost.”

The savings to patients and their insurance companies from taking lower doses of the drug would be significant, since the drug costs $5,000 a month.
“By taking one-fourth of the dose with a low-fat breakfast,” Szmulewitz said, “patients may be able to get the full medical benefit and save about $3,750 per month.”
The convenience would also appeal to patients. Many dislike having to fast for hours before and after taking their medication, which can upset an empty stomach. Since patients with advanced prostate cancer tend to be older, most take multiple medications for additional health issues, fitting each medication into a complicated daily routine. Many patients who take Zytiga wake up during the night, for example, to take the medicine, then go back to sleep, allowing them to eat soon after they wake up.

In the clinical trial, one-half of the study participants will take the standard 1,000 mg dose of Zytiga — four pills each morning while fasting. The other half will take one 250 mg pill each morning with a low-fat breakfast. All trial participants also will take prednisone, a steroid that helps prevent common side effects of Zytiga such as high blood pressure, low potassium levels and fluid accumulation.

Patients who are already taking Zytiga for prostate cancer should not “conduct such experiments on their own,” cautions co-investigator Mark Ratain, the Leon O. Jacobson professor of medicine and director of the Center for Personalized Therapeutics at the University of Chicago Medicine. The drug has not been carefully studied when taken with food. Careful monitoring of drug levels in the blood and its ability to stop or slow the growth of the cancer are central to the study.

“We do not yet know how well the drug will be absorbed or how it will impact the patient and his disease when delivered in this way,” Ratain said. “We know only what happens when it is taken on an empty stomach. In that setting, most of it gets flushed away at considerable expense.”

Zytiga Side Effects

Generally Zytiga is well tolerated with few side effects compared to standard chemotherapy. There are some side effects and these are related to the way it works to decrease the level of androgenic hormones. Zytiga inhibits androgen production in the body and this causes a type of male menopause when the testosterone levels fall to zero. This may result in symptoms such as hot flashes, feeling of faintness, dizziness and loss of balance in some cases.

In 50% of men there are no side effects reported and their responses to the drug have been very good. Some patients say they strated feeling better within a few days of taking Zytiga. Other men have seen their PSA plummet when on Zytiga seeing reductions in PSA from over 100 decline to less than 20 within a month in some cases.

In the remaining 50% the side effects are typical of androgen deprivation therapy. Many men may already have experience of these side effects from hormonal therapy having previously been on Lupron or Zoladex.

Here are the manufacturers guidelines on the side effects of Zytiga
About ZYTIGA

"Since its first approval in the U.S. in 2011, ZYTIGA has been approved in 39 additional countries, many thousands of men have received treatment with it, and it is quickly becoming one of the cornerstones of our oncology offerings," said Hait.

ZYTIGA in combination with prednisone was approved by the U.S. Food and Drug Administration (FDA) in April 2011 for the treatment of men with metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel.  The Phase 3 study for this initial ZYTIGA indication was also unblinded at the interim point, in August 2010, based on a statistically significant improvement in overall survival and an acceptable safety profile.  A subsequent analysis with more mature data confirmed the survival benefit and safety profile.
Indication

ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel.

Important Safety Information

Contraindications - ZYTIGA® (abiraterone acetate) may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess - Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI) - AI has been reported in clinical trials in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity - Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter.  Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient's baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

Zytiga Outperforms Provenge

I have been through Provenge, Taxotere, and am now on Zytiga. I also have stage IV metastatic progression to the bones. All PSA numbers are relative, but I will share my progression over the past 17 months. When Casodex quit having desired effect, my PSA rose to 20, and I was placed in a Provenge study that I took part in. After concluding the Provenge injection sequence, my PSA continued to rise. After three months, it had tripled to 59, so my oncologist and I decided that Provenge was not working and decided to move to taxotere (docetaxel). My PSA dropped into the teens and stabilized until the sixth and seventh courses, when it began to rise and I was reacting ( a couple of visits to the emergency room) adversely. In May of 2011, shortly after the FDA approval of Zytiga, I started the procedure of 4 tabs each morning...etc. May 18, my PSA was 29.99, June 15, it dropped to 2.91, July it was1.74, September it was 1.12, November .83, December 1.25, and just this week it was 2.05. I have had no noticeable side effects with the Zytiga, and have had continued improvement in energy and outlook. We hope the Zytiga continues to slow the cancer, as it is much easier to manage!
I have also started on a vegetarian diet to minimize "feeding" the tumors, which research indicates meat, dairy, and sugar accomplish. This diet also increases the intake of cancer fighting Salvestrols. I am not sure how much influence Provenge has had due to our early decision to move to taxotere, but I am confidant that the Zytiga has had a direct correlation to feeling better, lower PSA, and a brighter outlook on my future.

Structure of Abiraterone

Here is the chemical structure of Abiraterone (Zytiga). Note the 4 rings of the steroidal skeleton that are joined at the 17 position to a 3-pyridyl ring. The blue colour shows the nitrogen of the 3 pyridyl group that is responsible for its pharmacological action by binding to the iron atom at the centre of the CYP17 enzyme. The red colour shows the oxygen atom at the front end of the molecule. This mimics the oxygen of the natural substrate pregnenolone so Abiraterone fits the enyme active sit as precisely as the natural substrate but acts as an inhibitor through coordination of the central iron atom. In this way Abiraterone makes a precise fit into the CYP17 enzyme and inhibits it completely preventing it from making any androgens so the plasma androgen levels fall to zero when taking zytiga.

Inventor of Abiraterone Recommends Salvestrols

Abiraterone was discovered by Professor Gerry Potter in 1990 at the Institute of Cancer Research at the Royal Marsden Hospital in the UK. This is formulated as Abiraterone Acetate (Zytiga) for the treatment of metastatic prostate cancer. Ten years later Professor Potter discovered salvestrols which work against all types of cancer and are effective against prostate cancer. This has been formulated as the product Salvestrol Platinum which is recommended for all types of cancer.

For first line therapy salvestrols are useful since they do not suffer from any bad side effects, and are completely safe to take on a daily basis.

For patients relapsed on Zytiga or other hormonal therapies, salvestrols can be taken with good effect since they work by a hormone independent pathway.

Hopes Depend on Zytiga Approval by NHS

My husband has been on aberaterone for nearly four weeks and has an appointment next week for a check-up and hopefully will receive a further month’s supply of the tablets if all is well. The difference the drug has made to his symptoms and morale is amazing, even after this short time. We read yesterday’s NICE decision with sinking hearts and wonder whether his treatment will continue. If there is going to be a petition we will certainly sign it. For hope to be snatched away is cruel, for us and for many many others.

Zytiga Available on Greek NHS

My father has been suffering from prostate cancer for 20 and a half years. Over the years his body responded well to a variety of drugs and thanks to research he has been able to fiight his desease. He is currently 85 and taking Zytiga (Arbiraterone Acetate) in Greece through the Greek NHS system. It has cut his PSA count by half in 6 weeks! It has given him new hope and is able to enjoy life. He is currently not counting months.
I am surprised that in a country like the UK the NHS cannot find the money to help people when millions are squandered elsewhere.

Zytiga Extends Life by 6 Years

I started on the Phase II post-chemotherapy trial for Zytiga (Abiraterone Acetate) in 2006 at The Royal Marsden Hospital in the UK and I am still receiving benefit from the drug (as my only medication for prostate cancer) six years later. I have had very few side effects, none of them significant and little or no pain from the prostate cancer that had metastasised to my bones.
NICE is quoting four or five months as the time of average life extension. Be assured that I’m not the only man who counts the effectiveness received from the Abiraterone trial in terms of years rather than months – with a normal ‘quality of life’.
Others have raised the unassailable argument of how the UK government seems to have its priorities wrong when it comes to medical research and new drugs. I couldn’t agree more. Only 4 months ago NICE declined approval of Cabazitaxel. – Another drug researched and developed in the UK and shown to have proven benefit to certain types of prostate cancer.
Abiraterone (Zytiga) is now ‘standard treatment’ in many other countries so why should those in the UK, the country where these drugs have been discovered, researched and developed, be left out?
Such refusals by NICE must seem like hammer blows to the dispirited researchers and clinicians who have spent years of their lives working on the development of these new drugs. Who could blame them if they leave the UK to seek research posts in other countries where their work will be appreciated and put to the beneficial use of patients without quibble over cost.
Also, let’s not forget all those who have spent considerable efforts fund-raising so that these new drugs can be researched and developed in the first place.
In the UK we must maintain the pressure on NICE, MPs and Government ministers to ensure that this short-sighted decision is reversed so that the lives of many men, and the well-being of their families and loved ones, are saved.

The Story of Gerry Potter, The Discoverer of Zytiga

BY MARK SCHOLZ, MD

Zytiga has rapidly become the treatment of choice for prostate cancer resistant to standard hormone treatment with Lupron. It is effective and well-tolerated. Given the immense success of this product, I find the story of its discovery 22 years ago quite interesting. What follows is a heavily truncated version of Gerry’s story published on the web in 2010.

In 1990, Dr. Gerry Potter, having just finished his PhD, was in his first week of work at the Institute of Cancer Research in London's Royal Cancer Hospital. His colleagues on the drug discovery program, Prof. Mike Jarman and Dr. Elaine Barrie, wanted to target a male hormone-producing enzyme called CYP17 because prostate cancer feeds on testosterone.

A laser-guided bullet to target CYP17 was needed. Block this enzyme and you took away the cancer's exclusive food supply. "The idea was to starve the tumor to death, not attack it directly," explains Gerry.

They asked their new scientist to design a drug that “jammed”  the lock of CYP17. Easier said than done. To build a jamming key you needed to know what the lock looked like. No one did. You couldn't see it under a microscope. "You have to work it out from the inside," he says. "It's a bit like a glove. To know its shape, you need to understand the hand that fits it. You have a palm and fingers and thumbs. You have to work out how they all fit together."

Gerry worked on hunches and hypotheses, using his knowledge of the enzyme's basic components to scribble down different possible structures. Then he saw it, or rather he imagined it. "It was a Eureka moment," he says. "You instinctively know when something is right."

Now that he had the lock, he had to build the key to block it. That took a fortnight – a heartbeat in the time scale of hard science. "I developed a new chemical reaction to synthesize it," he says matter-of-factly. "What I was trying was really difficult and couldn't have worked predictably at any stage. Yet everything fitted into place. It worked first time."

Then came the boring part: the making of "analogues" –  a hundred near replicas of abiraterone, so no-one could make a copycat variant and claim the idea as their own. "None worked as well as the first," says Gerry, still slightly awed by that fact. "Everything came so easy."

Everyone involved felt the hand of history on their shoulders as abiraterone astonished participants in laboratory tests. The best prostate cancer drug on the market in 1990 – ketoconazole – had a cancer inhibiting activity of 10. "You need that number to be as low as possible," says Gerry. Abiraterone scored 0.001 – making it 10,000 times more potent than ketoconazole.

"It was, indeed, a magic bullet," says the scientist.

He "scaled up" the drug, so it could be produced in kilogram quantities – a requirement for the patent. The patent was eventually filed in 1994 through a venture capitalist company called BTG that had funded much of the supplementary research. BTG then sold on the team's hard work to Boehringer Ingelheim, a German pharmaceuticals giant with the financial muscle to support the fledgling drug through the inevitable years of clinical trials.

The people at Boehringer, however, became concerned when trials of abiraterone suggested it caused the depletion of cortisol, a hormone vital to health. The company cashed in its chips with abiraterone, selling the drug for $40 million to Cougar Biotechnology. Ultimately, pharmaceutical giant Johnson & Johnson (Janssen Biotech) bought Cougar Biotechnology for $1billion.  

Zytiga’s impact on lowering cortisol was easily solved by administering it with prednisone, a commercial form of cortisol.  Since Zytiga has so few side effects we have found safe ways to combine it with other effective therapies like Taxotere or Provenge.

Gerry and his team overwhelmingly succeeded in improving the lives of thousands of men with prostate cancer.

Zytiga Tablets

Zytiga Lowers PSA Dramatically

Hi I have been taking Zytiga for 4 months now and it is great, the drug has lowered my PSA from 165 to only 3 ! I am in remission now and I had stage 4 prostate cancer with bone mets. My recommendation is to take Zytiga (Abiraterone Acetate).

Abiraterone Shows Impressive Long Term Survival Benefits

Prostate Cancer Drug Abiraterone Shows Impressive Long Term Survival Benefits

New UK research confirms the groundbreaking cancer drug abiraterone provides significant benefit for up to two-thirds of men upon long term treatment for advanced and aggressive prostate cancer, according to a study published online in the Journal of Clinical Oncology.

The drug, discovered by Professor Gerry Potter at The Institute of Cancer Research (ICR) in the Cancer Research UK Centre for Cancer Therapeutics, made headlines in July 2008 when the first UK Phase I clinical trial reported significant shrinkage of patients’ tumours and reduction in pain. Scientists hailed it as one of the most significant developments in prostate cancer in 60 years. There is an 8 year survivor from the first Phase I trial started in 2004.

The second publication of a Phase I/II study, reporting on 54 patients, confirmed the Phase I results. In addition, ICR scientists have worked out how to delay drug resistance and developed a test to identify the men most likely to benefit from abiraterone. There are several 6 year survivors from recruitment in 2006 for the Phase II trials.

These Phase I/II studies were undertaken by the Institute of Cancer Research (ICR) and The Royal Marsden NHS Foundation Trust and were funded by Cougar Biotechnology Inc. The lead researchers on the study were funded by Cancer Research UK.

Lead researcher Dr Gert Attard says:

“Phase I/II results showed that up to 70 per cent of men responded to the drug, abiraterone. About two-thirds of men experienced significant benefits for an average of eight months, with scans showing their tumours decreased in size and their PSA levels dropped substantially.

“Our latest study also shows that by combining abiraterone with a steroid treatment when abiraterone stops working, we can reverse resistance and extend the response to this treatment by another 12 months.

 “We have also noticed that the majority of patients who had very significant shrinkage of their tumours had an abnormality of a gene called ERG that was probably driving their cancer. We have developed a test for this ERG gene so we can identify the men most likely to benefit from abiraterone.”

Chief investigator Dr Johann de Bono is extremely optimistic about these results:

“Almost all these men had cancer that had spread to the bones, lymph glands and elsewhere. Many were in pain and not enjoying life. The patients involved in this trial remained pain-free for an average of about eight months, a brilliant result for those with aggressive prostate cancer and their families. For about a third of men – those who carried the ERG gene - the benefit lasted for more than 18 months.

“In addition, this drug has changed the way the science community looks at prostate cancer. It can block the production of male hormones, including hormones produced by the tumour itself. The more we learn about how this drug works the more we will be able to find further ways of counteracting a patient’s potential genetic resistance to it.”

Mike Torr, 73 from Sheffield, was involved in the original Phase II abiraterone clinical trial in 2007. He says: "Five years ago, I was in severe pain as my prostate cancer had spread to my bones. I was involved in the earlier trials and received the additional steroid treatment to combat resistance. This drug has given me over five years of life, symptom-free. I have been able to go back to fully enjoying my retirement and travelling with my wife to places such as India."

Abiraterone is currently in Phase III prostate cancer trials at more than 200 hospitals across the world, in one of the largest ever trials for end-stage prostate cancer. More than 1500 men have been treated with the drug and it is hoped that, should the trials continue to show a benefit, abiraterone may be available for general use as a prostate cancer treatment in 2011.

Professor Peter Johnson, chief clinician at Cancer Research UK, which helped fund the lead investigators on the study, said: “These early results hold great promise for treating a problem which affects many men with prostate cancer and give us real hope for the future. We are keen to see the results of the larger trials now underway, to find out whether abiraterone should be made generally available. This drug is an excellent example of how research which leads to better understanding of the biology of a cancer can give us new opportunities for its treatment.”

Encouraging Feedback on Abiraterone

Hello all,
I am very happy to inform you all that today my father got his test back after 15 days using abiraterone and no predisone.
His initial PSA was 20.8 on 16th of January and today test show PSA of 5 !!!
His blood test show no significant change and all levels are withing normal range that is what the doctors said.
I had to share this news with you all.

Thanks
I just returned from a wonderful weekend with my father, he is doing great, his PSA is now down to 0.3 after being on zytiga for 2 months. With no problems related to liver function..... His last visit with the doctor was last week and the doctor's comment was that the resuts couldnot be better.
So i hope that the new treatment gives you great results, and please if you have any questions in specific i could ask my dad to answer them for you!

Hello
My father has a long journey with PC he was diagnosed in July 2004, and since then he had the RP with pathology 4+3 GS and pT3a G2 M0 N0 with post op. PSA of 0.82 and had salvage radiation ....... and was on hormone therapy Eligard + Casodex until that was no longer working than he started chemo in october 2009
1.October 2009 (Docetaxol + predisolone) 4
infusions 3 weeks a part ( PSA at beginning of
chemo 5.2 and drops till 0.80) than climbs again to 5.7
2.July 2010 (Docetaxol + predisolone) 4 infusions
3 weeks a part (PSA at beginning 5.7 and drops to
0.70)
When chemo was seen to not work he staid with no treatment (only the Eligard shot) for a year where his PSA went to 20.8 and started Zytiga.

Hi
After Taxotere there are other treatments available right now such as salvestrols.
I started Zytiga and predisone a few weeks ago. The predisone has spiffy side effects such as hard to sleep through the night, but those can be eased with fairly simple solutions such as red wine and melatonin, or Ibrubrofen.
Their is at least two threads that talk about predisone. From the Zytiga - seems to me no side effects I have noticed. One potential is the Zytiga can affect the liver, but that is something which I've had checked via blood work as part of the treatment. From what I gather, Zytiga affecting the liver is possible but fairly rare.

News Just Gets Better for Abiraterone

The news just keeps getting better for Johnson & Johnson's new prostate cancer drug Zytiga (abiraterone). Investigators unblinded a late-stage study of the drug--plus prednisone--for prostate cancer victims who had not been treated with chemotherapy. The blockbuster drug is already approved for treatment-resistant cases and the news heralds a quick-step expansion of the prospective patient population.

Johnson & Johnson ($JNJ) says the independent monitoring committee members for the study were satisfied that they had the results they were looking for on progression-free survival as well as the co-primary endpoint of overall survival along with key secondary endpoints. The move paves the way for J&J to start filing for expanded use later this year.

According to Adam Feuerstein at TheStreet, a J&J spokesperson confirmed that investigators had established a statistically significant response for PFS and a "strong trend" on OS, though the data in that category was not statistically significant. The independent data monitors "stopped the trial based on the totality of the data they saw," Kellie McLauglin told TheStreet, which included a statistically significant benefit for all secondary endpoints.

Zytiga has a reputation as a faster acting, more convenient therapy for prostate cancer--quick to ease pain and other effects of cancer--has spread among patients and physicians.

"This study has been a key priority for us as we expand our understanding of the utility of Zytiga in metastatic prostate cancer," said William N. Hait, the global chief of Janssen R&D. "We're delighted that these data will soon be added to the growing body of literature about this important medication."

Abiraterone Gives Hope

Published on Saturday 17 March 2012 17:00

A TERMINALLY ill cancer patient is following his beloved Chesterfield FC to Wembley, thanks to a life-extending drug not widely available on the NHS.

Rick Betton, 57, who was diagnosed with prostate cancer in 2010, said he is able to enjoy life thanks to the £3,500-a-month treatment, abiraterone – that he gets through his employers private health care plan.

But Rick, who will be cheering the Spireites on in the JP Trophy final with son, Ryan, 28, wants the NHS to reconsider its provision of the drug.

“It prolongs your life” he said. “I have been on it since November and it helps me get out and about. I had two lots of chemotherapy before and both worked for a while, but this was my last stop. With this new drug my life is open ended. It’s the price of life.”

He added: “Before I lost all my hair and was too tired to go out really. Now I can go out, I just went to visit my daughter in Bath. It’s enabling me to go to Wembley.”

Rick will make the trip down to London on March 25 from the home he shares with his wife, Rachel in North Wingfield.

Weekly trips

He said: “I was six when I saw them play for the first time and I still go each week. I decided to get a season ticket in the new ground and I have kept it going.

“We all went to the game in 1997 when we were robbed. Then we got hammered in the replay.”

Ryan – one of Rick and Rachel’s four children – added: “My first ever game was at Wembley with my dad, against Cambridge and we lost. We are going back to where it all started, hopefully we will have better luck.”

Rachel, who will be at home on match day, said: “It’s hard to put in words but the drug is a life line and it has given us hope. It makes him be himself because that is who he has always been. He has always been a football fan and now he can still be that.”

A spokesperson for NHS Derbyshire County, said: “Abiraterone is funded by the Cancer Drugs Fund for patients who meet the criteria. Individual funding requests can also be made to NHS Derbyshire County under its Individual Funding Request policy.”

A man with prostate cancer has said a drug he has been taking has given him his life back and is campaigning to keep it funded by the NHS.

Hugh Gunn, from Countesthorpe in Leicestershire, had had a failed course of chemotherapy and said he was too weak to put the rubbish out but within two days of taking Abiraterone he said his health started to improve.

The drug is only funded for another two years on the NHS and the National Institute for Health and Clinical Excellence, the body that advises the NHS, has issued draft guidance saying it does not provide value for money.

Leicestershire cancer patient to get abiraterone

Hugh Gunn said getting abiraterone to treat his advanced cancer gave him hope for the future

A Leicestershire cancer patient has described the news that he is to receive a potentially life extending drug as the "best present ever".

Hugh Gunn, from Countesthorpe, had previously been refused abiraterone after multiple sessions of chemotherapy failed to treat prostate cancer.

The NHS East Midlands Strategic Health Authority had said funding for the drug was not clinical and cost effective.

But it has now reversed its decision after a case was presented to a panel.

The NHS said that after evidence was given on the "clinical benefits" of abiraterone at a review meeting, the medicine was approved and added to the region's drug list.

Positive future

Mr Gunn said: "Being on this drug now gives me hope for the future, before I was feeling hopeless."

Mr Gunn, who was diagnosed with prostate cancer on Christmas Eve in 2005, was recently told he had only had months to live.

"Without this drug I was very much at the end, abiraterone turns it into a chronic liveable disease from a terminal disease," he said.

Mr Gunn's wife, Kate, said they were "so thrilled" and could not believe that he was now getting abiraterone to treat his advanced cancer.

Mrs Gunn said the family could now enjoy the festive period and look forward to a more positive year ahead. One in which Hugh could "look forward to living life".

Zytiga Success

Abiraterone (Zytiga) does not work for everyone with prostate cancer. But in over 70% of men it does work to lower PSA and cause tumour regression without harmful side effects. In over 50% of cases the response can be dramatic and some people respond exceptionally well to Zytiga. Here is an example that came out in the UK press yesterday:

Ron McCoo Aged 59

“I’ve taken all sorts of treatments including Zoladex, Taxotere and Cabazitaxel, but all of them stopped working after a while so I started Abiraterone in November. I noticed an immediate difference in my health.

It gave me more strength. I wasn’t as tired and I actually didn’t feel ill. I didn’t seem to get any side effects.

Now I no longer need liquid morphine, which I previously used to cope with the pain.

My wife Terri has also noticed a change in me — we can sit, talk and go out for walks which I couldn’t do before because I would get out of breath.

I’ve got another three months’ supply of the drug and feel extremely lucky.

I know that a lot of other people can’t get Abiraterone. If you can’t afford to pay for it, you just go and die. For me it’s wrong. Their reasoning is for the extra four months you might get it’s not worth it but for me and my family it’s worth more.

I was able to enjoy my great-granddaughter’s first Christmas — something I didn’t think would have been possible before — and I hope we will all be together for her first birthday too”.