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In an utterly unsurprising announcement from the UK, the National Institute for Clincial Excellence (NICE) has issued draft guidance in which it refuses to cover the proposed cost of abiraterone actetate.
This draft guidance looks suspiciously like the first round in a negotiating process with the manufacturer of abiraterone acetate.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.