Abi Comes of Age

2012 has seen a series of regulatory approvals worldwide for Abiraterone Acetate, affectionately known as "Abi", and now marketed by Johnson & Johnson as "Zytiga".

In 2012 Abi was approved by all the main regulatory authorities throughout the world, having been approved by the FDA, EMA and TGA.

May saw the COU-302 phase 3 trial results announced at the ASCO conference in Chicago, which paved the way for the submission for FDA approval for use before chemotherapy.

On June 26th it was announced that the drug rationing watchdog NICE had approved Abi for use on the NHS for free prescription use in the UK.

On 10th December this year the FDA approved Abi for use in treating prostate cancer before chemotherapy.

Neoadjuvant Zytiga Eliminates Prostate Cancer

Zytiga can completely eliminate prostate cancer when given early enough as first line neoadjuvant therapy before surgery. A clinical trial has been conducted to evaluate the benefits of Abiraterone Acetate (Zytiga) when given early on, in the neoadjuvant setting before surgery. The results of this trial look very promising with results showing prostate cancer being eliminated in 10% of patients, and almost completely eliminated in 30% of patients, after 6 months of neoajuvant Zytiga.

Here are the testimonials of two prostate cancer patients who took part in the clinical trials of neoadjuvant Zytiga.

Patient #1

My PSA went up from 2.4 in 2004 to 3.9 in August, 2009 - that triggered a visit to specialist.

Biopsy done in November, 2009 - Gleason score of 8.

MRI in December, 2009 confirmed the cancer had spread outside the prostate.

February 12, 2010 I started the Abiraterone Trial.

Within one month my psa was down to 0.64.

By May 12, 2010 my psa was down to 0.02.

My surgery was on August 5, 2010.

On August 18, 2010 my doctor told me the results of the pathology report - 0.0% residual cancer.

From pathology report post-surgery - left pelvic lymph node negative; right pelvic lymph node negative; prostate - no residual prostatic adenocarcinoma

I lost 42 pounds
My cholesterol improved dramatically
My CRP level is now normal
I had surgery August 5th to remove the tumors
On August 18th my doctor informed me that there was 0.0% (none, nada) residual cancer

Bob

Patient #2

I was in the same trial and had similar results. A little history:

I was 59 when diagnosed. I had my annual check in July 2010. The DRE revealed a lump and my PSA was 19. The biopsy revealed Gleason grade 7 (4+3 and cancer in 7 of the 12 cores). An MRI also showed a suspicious lymph node in, as the doctor said, a strange place well away from the normal prostate drain field.

My treatment has entirely taken place at Seattle Cancer Care Alliance (Univ. of Washington Medical Center & Fred Hutchinson Cancer Research Center)under the care of Dr William Ellis (surgeon) and Dr James P. Dean (medical oncologist). I took part in a clinical trial of pre-adjuvant Abiraterone & Lupron plus Prednisone. This lasted 6 months. I then had an open radical prostatectomy on March 1, 2011. Surgery was required by the study, but it could be either robotic or open. I had open because of the suspicious lymph node. The surgeon wanted to do a very thorough surgical lymph node resection. The pathology report showed clear margins, no seminal vesicle invasion, no extracapsular invasion and no lymph node involvement. The suspicious lymph node showed that the clinical trial had an effect--there was evidence of inflammation which is present when a cancer has been destroyed. No active cancer was found. Because of the use of Abiraterone and Lupron, the pathologist cannot determine a post surgery Gleason score. The treatment effect makes that impossible. I have since had one PSA test with an undetectable result (>.03 at this lab. My next test is June 8th.

The side effects of both Abiraterone and Lupron are similar and were manageable for me. I had (and still have) hot flashes. Weight control was very difficult, although I only gained about 7 pounds. Libido drops to nothing as does potency. Fatigue was the primary problem, but it was manageable and I was able to work full time and continue with life as normal during the study. I had blood tests every two weeks.

Now that the treatment phase of this is over, I'm working with our daughter who is a registered dietician to make sure that I eat a very healthy diet. The weight is starting to come off and that should get easier as the testosterone continues to come back into my system. A good support system is vital. My wife is a breast cancer survivor so we knew the drill when this happened, but it is still a rough road.

I knew that I had an aggressive cancer so I wanted the most aggressive treatment. I didn't hesitate to take part in the trial as I wanted to bring every weapon possible in this fight.

John

How Fast Does Zytiga Work

Zytiga works very fast in its pharmacological action of lowering testosterone working within 30 minutes of being taken. Following oral administration Zytiga is absorbed by the small intestine into the bloodstream and starts working within 30 minutes and its effects last longer than 24 hours. It has a half life of 12 hours. So after 12 hours the plasma concentrations have reduced by half which is still an active concentration. So Zytiga is rapidly absorbed and starts inhibiting the enzyme CYP17 which blocks all androgen production within a few hours. The testosterone levels then gradually reduce down to zero over the next few days and have reached their lowest within a week. This brings about total androgen deprivation (TAD) which prevents androgen receptor positive prostate cancer cells from growing and the absence of androgens promotes tumour cell death by apoptosis.

The effects of total androgen deprivation is different in each case. Some men respond quickly to TAD whilst others do not respond at all and their PSA continues to rise. In some cases a sharp rise in PSA is seen initially following Zytiga treatment but then reduces after 2 months. In order to evaluate the efficacy of Zytiga it is best to look at the PSA trend over 3 monthly tests. This gives a clearer idea of the response since any initial increase should have subsided after the second reading and declined further after 3 months.

Zytiga to be Trialled as First Line Therapy

A three arm clinical trial has started looking at comparing Zytiga plus Prednisone alone, versus Zytiga plus Prednisone in combination with Degarelix, versus Degarelix alone for men who have received surgical prostate removal but the PSA has started to rise.

This will be the first time the Zytiga Prednisone Combo (ZPC) alone has been tested as the first line therapeutic option once surgery has failed.

Degarelix is a new LHRH antagonist given as a monthly injection and has similar activity in lowering testosterone levels to the LHRH agonists Lupron and Zoladex. Zytiga is taken as 4 x 250 mg tablets daily together with 5 mg of Prednisone daily. This is not a blinded trial since the patients will know if they are taking daily tablets or receiving a monthly injection.

Degarelix does not stop androgen production altogether and low levels of testosterone can be detected in the plasma of patients taking Degarelix. In contrast Zytiga inhibits CYP17 to bring about total androgen ablation as a single agent so Zytiga alone should work better than Degarelix alone and the combination of Degarelix with Zytiga will possibly be no better than Zytiga alone making since mechanistically speaking Zytiga makes Degarelix redundant.

Zytiga Increases Overall Survival When Used Earlier

The latest results from the COU-302 Phase 3 clinical trials of Abiraterone Acetate (Zytiga) show that Zytiga does indeed extend overall survival to a greater extent when used earlier in the treatment of this disease. This trial carried out on patients who had failed androgen deprivation therapy (ADT) but not requiring chemotherapy. The Zytiga Prednisone Combo (ZPC) arm had an overall survival of 35.3 months versus 30.1 months for the Prednisone plus Placebo arm. This equates to an extension of overall survival of 5.2 months which is the longest time for an agent tested in this category of patients. This compares to an OS extension of 4.6 months when used post chemotherapy. Maybe if Zytiga was used even earlier in the treatment of prostate cancer such as first-line neoadjuvant therapy the OS extension may be even greater.

Provenge Vs Sodium Bicarbonate

Which is the best treatment for prostate cancer Provenge or Sodium Bicarbonate. Well it turns out that according to patient testimonials easily available on the internet by searching on "provenge cancer testimonials" and "sodium bicarbonate cancer testimonials" that good 'ol baking powder (Sodium Bicarbonate ) comes out on top.

Xtandi Zytiga Jevtana Provenge Which is What ?

Anyone listening to the news has heard of new drugs for prostate cancer heralded as a golden era in drug development. First came Provenge the autologous immunotherapy vaccine that is supposed to lengthen overall survival (OS) by 4.2 months. Then came Jevtana, a new form of Taxol therapy active against Docetaxel resistant prostate cancer giving an OS benefit of 2.3 months. Then came Zytiga extending life by 4.6 months and finally the new kid on the block Xtandi with an OS of 4.8 months. But what are all these drugs and how do they really perform in clinical practise. Heres a summary of their attributes.

Provenge $93,000 per treatment consisting of 3 injections of a dendritic autologous witches brew concocted out of your own white blood cells delivered by a port which is inserted into the abdominal cavity.

Demostrated Benefits: None proven

Side Effects: Loss of money

Jevtana $24,000 for course of chemo injected by infusion over 1 hour.

Side Effects: Peripheral Neuropathy (Numbness), Hair Loss, Nausea, Liver Failure

Zytiga $60,000 per year for 4 tablets daily.

Side Effects: Hypokalaemia (Low Potassium) corrected by Prednisone

Xtandi $89,000 per year for 4 capsules daily

Side Effects: Seizure onset after 28 days.

FDA Approves Zytiga Pre Chemotherapy

The FDA have approved Zytiga for use before chemotherapy it was announced today. This is tremendous news and puts Zytiga in its rightful place as a treatment option once conventional androgen deprivation therapy (ADT) has failed but before chemotherapy is needed. Zytiga is the actually the ultimate form of ADT since it induces total androgen blockade by inhibiting the biosynthesis of all androgens, so it makes sense to use Zytiga when less effective forms of ADT such as LHRH agonists have failed. Zytiga was designed as a safer option than chemotherapy so it is appropriate that Zytiga is now approved before the use of chemotherapy.

The FDA approval was based on the results from the COU-302 phase 3 clinical trials conducted on patients who had not received chemotherapy. The announcement from The FDA is as follows.

FDA expands Zytiga’s use for late-stage prostate cancer
Drug can now be used before treatment with chemotherapy
The U.S. Food and Drug Administration today expanded the approved use of Zytiga (abiraterone acetate) to treat men with late-stage (metastatic) castration-resistant prostate cancer prior to receiving chemotherapy.
The FDA initially approved Zytiga in April 2011 for use in patients whose prostate cancer progressed after treatment with docetaxel, a chemotherapy drug. Zytiga is a pill that decreases the production of male sex hormone testosterone.
In prostate cancer, testosterone stimulates prostate tumors to grow. Drugs or surgery are used to reduce testosterone production or to block testosterone’s effects. Some men have castration-resistant prostate cancer, meaning the prostate cancer cells continue to grow even with low levels of testosterone.
“Today’s approval demonstrates the benefit of further evaluating a drug in an earlier disease setting and provides patients and health care providers the option of using Zytiga earlier in the course of treatment,” said Richard Pazdur, M.D., director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research.
The FDA reviewed Zytiga’s application for this new indication under the agency’s priority review program. The program provides for an expedited six-month review for drugs that may offer major advances in treatment or provide a treatment when no adequate therapy exists.
Zytiga’s safety and effectiveness for its expanded use were established in a clinical study of 1,088 men with late-stage, castration-resistant prostate cancer who had not previously received chemotherapy. Participants received either Zytiga or a placebo in combination with prednisone.
The study was designed to measure the length of time a patient lived before death (overall survival) and the length of time a patient lived without further tumor growth as assessed by imaging studies (radiographic progression-free survival, or rPFS).
Patients who received Zytiga had a median overall survival of 35.3 months compared with 30.1 months for those receiving the placebo. Study results also showed Zytiga improved rPFS. The median rPFS was 8.3 months in the placebo group and had not been reached for patients treated with Zytiga.

Identification of a New Zytiga Resistance Pathway

A new resistance pathway to Zytiga therapy has emerged which involes signalling by the enzyme MAPK4 which is a MAP Kinase that upregulates androgen receptor (AR) expression and mediates tumour growth signalling via an androgen independant pathway. Hence hormone resistant prostate cancer is able to able to overcome total androgen blockade by Zytiga and continues growing by signals mediated by MAPK4. Therefore inhibitors of MAPK activity have potential to overcome Zytiga resistant prostate cancer (ZRPC) and should be considered as clinical candidates for use in combination with Zytiga, as well as for use in treating Zytiga relapsed patients.

MAPK4 is activated by phosphorylation by the enzyme p21 Activated Kinase (PAK) which is itself activated by the small GTP binding proteins p21 Rac and Rho. Thus the MAP4K signalling pathway proceeds along the route Rac-PAK-MAPK4-AR which offers several angles for therapeutic intervention by inhibition of Rac, PAK, or MAPK4 itself.

A selective inhibitor of MAPK4 has been identified called SB203580 but this has not been clinically tested. Pfizer have identified a potent inhibitor of PAK kinase with an IC50 of 1.3 nM, named PF-3758309. This drug shows exciting anticancer activity in pre-clinical models and is a drug candidate for human clinical trials. This has been a very well designed drug that snugly fits the cleft of the substrate binding pocket. Natural inhibitors of PAK kinase have been identified including propolis, resveratrol and salvestrol T30.

Molecular structure of PF-3758309 showing the (S) chiral phenyl substituent which fits precisely into the binding pocket.

BKM120 Zytiga Combo

BKM120 is a potent inhibitor of PI3K which augments total androgen blockade with Zytiga. PI3K mediates the cell survival pathway by inhibiting apoptosis (cell death). Insulin signals this survival pathway through the IGFR receptor which signals through the IGFR-PI3K-PIP2-Akt pathway to generate active phospho pAkt which phosphorylates the FOXO transcription factor to inactivate it. FOXO transcribes the apoptotic proteins so inhibiting FOXO by active Akt prevents cells undergoing apoptosis and keeps these cells alive. So the prostate cancer cells are surviving on insulin by signalling through the IGFR/PI3K/Akt pathway. No wonder inhibitors of this pathway are important since they will induce apoptosis of cancer cells causing tumours to regress. In practice PI3K inhibitors do not work very well when used alone but do work well when combined with other treatments. Clinical trials show that BKM120 increases the response rate when comibined with Paclitaxel. In fact there are several ongoing clinical trials with BKM120 against various forms of cancer including prostate cancer, breast cancer and lung cancer.

There is emerging evidence that cancer cells surviving Zytiga therapy are doing so by using this insulin promoted singalling pathway of PI3K/Akt so using a PI3K inhibitor in combination with Zytiga makes perfect sense. The natural PI3K inhibitor salvestrol Q40 is present in Salvestrol Platinum which has been combined with Zytiga with promising results. The pharmaceutical industry are now catching up with mother natures PI3K inhibitors. The semi synthetic PI3K inhibitor PX-866 is a derivative of the natural compound Wortmanin which is also in clinical trials in combination with Zytiga. Many drug companies are now jumping on the bandwagon and several new drug candidates are in progress that inhibit members of the PI3K-Akt-mTOR pathway. Clinical trials are now underway to evaluate the combination of BKM120 with Zytiga.

BKM120 is from Novartis Pharmaceuticals who have succeeded in producing a really well designed drug that has activity against all 4 isoforms of PI3K inhibiting the catalytic subunits p110 alpha, beta, gamma, and delta with IC50's from 30 to 160 nM.

The molecular structure of BKM120 shows that it is a di morpholino substituted pyrimidine. It has a half life of 40 h with a maximum tolerated dose of 100 mg daily. No significant side effects were reported from trials on BKM120 and show this drug is well tolerated.

Zytiga Use Before Chemotherapy Makes Sense

Zytiga therapy fits most naturally into the treatment strategy for prostate cancer before chemotherapy is used. It is far safer than chemotherapy and so should be used first. Zytiga is a form of hormone therapy that is capable of total androgen ablation and so it makes sense to use Zytiga after other forms of androgen deprivation therapy (ADT) have failed but before chemotherapy is needed. This is the subject of the current sNDA application for FDA approval of Zytiga before chemotherapy. The EMA committee on medicine use in humans has already recommended Zytiga after ADT has failed, i.e. before chemotherapy, and this should lead to EMA approval in Europe early next year.

Presently the FDA approval is limited to use of Zytiga after chemotherapy has failed. This has led to the use of chemotherapy to qualify for Zytiga treatment which is a consequence of the current legislation. Zytiga can presently be used off-label at the Doctors discretion for the treatment of prostate cancer before chemotherapy but this is not generally covered by insurance companies until it is FDA approved in this category.

Was Provenge FDA Approval Based on Suspect Data ?

The FDA approval for Provenge was based on clinical data that showed a 4 month increase in survival showing a 25.8 month survival with Provenge compared to 21.6 months for the placebo injection. However the placebo injection has come under scrutiny and probably reduces survival which shows a false life extension.

This anomoly is highlighted by results from the latest Zytiga trial which showed that patients who were treated with the placebo lived for 27.2 months which is actually longer than people treated with Provenge. So a true placebo shows a survival of 27.2 months, Provenge shows a survival of 25.8 months, and the Provenge Placebo group had a survival of 21.6 months. These figures clearly show that the Provenge Placebo is toxic and actually causes decreased survival. In view of this decreased survival using a Provenge Placebo vaccine raises issues about the ethics of giving such a treatment to terminally ill men with prostate cancer.

Does Provenge Work for Men with Prostate Cancer ?

Does Provenge Work for Men with Prostate Cancer - Well the short answer is No ! There is as yet no clinical evidence for the Provenge vaccine working in practise and men treated with Provenge continue to experience rises in PSA and disease progression.

This same question was asked on a website www.prostate.net
that is promoting Provenge and other bogus treatments such as "Prost-P10X" and prostate cancer sufferers should be wary of the products peddled on this website and the information it contains which encourages allopathic approaches such as surgery radiotherapy and provenge.

So far the only testimonials relating to Provenge use appear to be negative and here is one example.

Provenge Testimonial

"I spent the day having CT and Bone scans, then talking with ONC about the results. Apparently Provenge did absolutely nothing. I have a couple of new mets and PSA has gone from 14 at time of Provenge treatment to 49 two months later. What a bummer.
That is $93,000, a bunch of time and a couple of crappy days down the drain for nothing.
Has anybody heard of Provenge doing nothing? I knew it was not a cure, but I thought it would buy me six months to a year before having to do something else.
ONC says I either need to start on Taxotere or get into a trial. I do not want to do Taxotere, but she says if I do one treatment and claim I can not tolerate it I can then start Zytiga. That is probably what I will do.
Has not been a good day.
Some days you are the pigeon and some days you are the statue. Today I know which one I am.

I know Provenge does not necessarily effect one's PSA. However, you should not get new metastases after you had it, and any bone mets you already have should not get any worse. In just two months since I was treated the metastasis I already had got worse and new ones appeared. That is a sure sign that Provenge did not work. I have spoken with two Oncs about this and they agree that this should not be happening. Regardless of what your PSA does you will not live long if you continue to get new and bigger mets. You can not sit around hoping maybe it will start working in a month or two.

Needless to say I am very disappointed that Provenge did not perform as advertised in my case. I was counting on it to give me a year or so before I had to move on to another treatment. By then I was hoping that MDV3100 would be approved and who knows what else may come along.

Knowing what I knew in March I would do it again. However, at this point it was as I said a waste of time, money, and a lot of people's efforts. All the research I did beforehand never mentioned that some people got zero benefit from it.

However, the Onc I saw today, who is the biggest Provenge guy here in the USA, told me he has about 25% of the patients he has treated get no benefit from Provenge."

Norm

EMA Committee Recommends Zytiga Before Chemotherapy

The European Medicines Agency (EMA) advisory body the CHMP have recommended Zytiga for use before chemotherapy in treating prostate cancer. This paves the way for final EMA approval which is expected soon. Zytiga is also undergoing consideration by the FDA for use before chemotherapy. This will help thousands of men who have been looking forward to this approval.

CHMP backed expanding the label of Zytiga (abiraterone acetate) to include treatment in combination with prednisone or prednisolone of chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (CRPC) who are asymptomatic or mildly asymptomatic after failing androgen deprivation therapy. Zytiga is under Priority Review by the FDA for this indication in the US, with a decision date expected in December. Zytiga is already approved in the US and EU in combination with prednisone to treat metastatic CRPC patients who have received prior chemotherapy containing docetaxel.

Zytiga Approved in Ireland

Zytiga has at long last been approved for use in Ireland as from the 1st of December 2012. Initially this treatment, also known as Abiraterone was rejected by the Irish regulatory board NCPE (National Centre for Pharmaco Economics) on cost grounds. However after negotiations with the manufacturer Johnson & Johnson a reduced price has been agreed meaning that this treatment will now be available in Ireland. From 1st of December Zytiga will be available on the national health system for use to treat advanced prostate cancer in men who have relapsed following chemotherapy.

Professor Gerry Potter the inventor of Zytiga has recently been on a lecture tour of Ireland visiting Dublin, Cork and Galway finally giving a public talk to the Ballinasloe Cancer Support Group on the discovery of Zytiga and Salvestrols. After the talk Prof Potter said "I am delighted that men in Ireland can now benefit from Zytiga and all the research that we have done. Hopefully Zytiga will be approved soon for use as an earlier treatment before chemotherapy is even needed".

Medical professionals have hailed the news that Zytiga will soon be available in Ireland as really good news. It can prolong the lives of some of those suffering from the disease. The once-daily oral medication is proven to keep patients alive and improve quality of life for some men in the advanced stages of the disease. Zytiga will be used with a steroid for post- chemotherapy of prostate cancer that has spread to other organs in the body.
It is the second most frequent male cancer and claims the lives of 500 men a year in Ireland alone.
There are almost 17,000 suffering with the disease at the moment and Ireland has the highest incidence in Europe. Consultant oncologist at Tallaght and St Vincent's Hospital Dr Ray McDermott said it is huge progress for prostate cancer sufferers here.
He added: "This is great news for Irish patients and their families.
"Up to now there has been no active treatment available for patients with advanced prostate cancer whose cancer has progressed after chemotherapy so this new treatment represents a real un-met clinical need." The drug will be reimbursed by health authorities here from December 1. John Dowling from the Men Against Cancer said it will give patients precious months more to live.
He added: "Men with advanced prostate cancer, if suitable, may now be offered treatment with abiraterone which may give them the real prospect of precious additional months over current treatments together with a reasonable quality of life."
.
In Ireland, prostate cancer is the most frequent cancer in men after non-melanoma skin cancer. There are more than 17,000 men living with prostate cancer in Ireland and approximately 500 die from the disease each year.

Zytiga (abiraterone acetate) was approved originally for patients who had relapsed after multiple forms of ther-apy, including chemotherapy. Approvals following the initial COU-AA-301 Phase III study (the ‘301 Study’) were based on results from an interim analysis showing a statistically significant improvement in overall survival and an acceptable safety profile. Zytiga, in combination with prednisone, was approved by the European Medicines Agency (EMA) in September 2011 for the treatment of metastatic, castration-resistant prostate cancer (mCRPC) in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen.
“As of this moment, abiraterone acetate is not available to patients in Ireland. However, I keenly await its arrival,” Dr Ray McDermott, Consultant Medical Oncologist at St Vincent’s University Hospital and Tallaght Hospital, Dublin, said.
The drug is currently licensed for more advanced patients, who have already received chemotherapy. Its manufacturer, Janssen, is currently in talks with the National Cancer Control Programme on reimbursement for patients, similar to those in the 301 Study.

Shows great promise
Dr McDermott said: “This is an oral agent which shows great promise for patients with advanced prostate cancer, is well tolerated and improves quality of life.”
In addition, an application to the EMA’s Committee for Medicinal Products for Human Use (CHMP) is intended to extend the use of abiraterone acetate administered with prednisone for the treatment of patients with mCRPC who are asymptomatic or mildly symptomatic, after failure of androgen deprivation therapy and before chemotherapy.
Submissions have been made, based on Phase III results, which show “significant improvement” in radiographic progression-free survival and a trend for increased overall survival in patients receiving Zytiga plus prednisone.
The COU-AA-302 trial (the ‘302 Study’) was for patients who had progressed on androgen deprivation therapies but had not yet received chemotherapy.
This study, which included 1,088 asymptomatic or mildly symptomatic men with mCRPC who had not received chemotherapy, evaluated the effect of abiraterone acetate plus prednisone on the co-primary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) compared to placebo plus prednisone. Data from this study were presented at the 48th Annual Meeting of the American Society of Clinical Oncology (ASCO).

The study was designed with patients in mind who had progressed after standard androgen deprivation therapy. In most parts of the world, this involves either medical (with LHRH agonists) or surgical castration.
Often, an anti-androgen such as bicalutamide is added. When patients progress, further treatment with hormonal agents is often attempted. Some patients who have progressed after androgen deprivation do wish to receive chemotherapy. “Zytiga could prevent patients with known castration–resistant, metastatic prostate cancer  from getting chemotherapy for quite a while,” Dr Bill Hait, Global Head, Janssen Research and Development and Head of the firm’s Oncology Therapeutic Area, proposed.
During an interim analysis, the independent data monitoring committee advised that the study be closed prematurely because of the benefits seen in the Zytiga arm.
“There were remarkable improvements in measurements of clinical benefits, including progression-free survival, time to chemotherapy and opiate use,” said Dr Hait.
In terms of radiographic progression-free survival, in the control arm, the median was 8.3 months. In the Zytiga arm, the median had not yet been reached. There was at least a doubling of freedom from progression. “A 33 per cent improvement has already been observed in median overall survival; in the Zytiga arm, the median still has not been reached. In the control arm, the median was 27 months,” Dr Hait said.
There are a number of other new treatments in the oncology drug development pipeline and the strategy which led to Zytiga has yielded further therapies such as Salvestrols which are also now available in Ireland.

AT-13387 Zytiga Combo

AT-13387 is a novel inhibitor of HSP-90 a chaperone protein which stabilises a number of cellular proteins including the androgen receptor (AR). Upon HSP-90 inhibition the AR undergoes decomposition and cannot function in cell signalling. This interuption of AR stimulated signal transduction results in the death of prostate cancer cells and so HSP-90 inhibitors have therapeutic potential in the treatment of prostate cancer.

Zytiga is now widely used in prostate cancer therapy and a combination trial of AT-13387 with Zytiga is currently underway. AT-13387 is produced by Astex Therapeutics a forward looking new enterprise in oncology with several exciting new lead compounds with promising preclinical anticancer activity. The combination of AT-13387 offers a two pronged approach at blocking androgen receptor mediated prostate cancer growth and should work very well together.

Molecular structure of AT-13387 shows a cresol group which mimics the natural HSP-90 inhibitor salvestrol Q40.

Studies have shown that HSP-90 inhibition with salvestrol Q40 results in degradation of important signal transduction proteins such as the STAT kinases that ultimately leads to apoptosis and cancer cell death. Molecular modelling studies show that salvestrol Q40 inhibits HSP-90 by neatly locking in to the ATP binding site. Therefore HSP-90 inhibitors have promising potential for the treatment of a variety of cancers including prostate cancer and trials of HSP-90 inhibitors against breast cancer also look promising.

Importance of PI3K Signalling in Prostate Cancer

Inhibition of the PI3K pathway is an important therapeutic approach for the treatment of prostate cancer. Signalling by the PI3K/Akt/mTOR pathway plays an important role in the survival mechanism of prostate tumours and it is this signalling that is keeping the prostate cancer cells alive. Inhibit this pathway and the cancer cells automatically undergo apoptosis which is programmed cell death. It has been shown that the natural PI3K inhibitor salvestrol Q40 results in reduced downstream phosphorylation of Bcl-2 causing elevated Bax to Bcl-2 ratios that result in apoptosis. Furthermore Zytiga drug resistance pathways are mediated by the PI3K pathway and so inhibitors of PI3K such as salvestrols can be used to overcome Zytiga resistance. A number of different PI3K inhibitors are under clinical investigation in combination with Zytiga.

PI3K Signalling Pathway in Prostate Cancer

Prostate cancer is the second highest cause of male cancer related mortality. Currently the main aim of   therapy for localised and metastatic disease is total androgen blockade. This aim has been achieved with Zytiga which inhibits all androgen production, thereby reducing stimulation of the androgen receptor (AR). This in turn prevents the activation of androgen-regulated genes, which normally result in on-going growth and survival of particular interest in this survival mechanism is the continued signalling by the PI3K pathway. Inhibition of testicular androgen production may be achieved surgically (bilateral orchidectomy) or chemically, using LHRH agonists. The latter induces castrate levels of testosterone by down-regulating pituitary LHRH receptors (and therefore gonadotropin hormone production) through constant stimulation. The action of androgen may be blocked at a peripheral level using anti androgens such as Casodex and Enzalutamide, which inhibit ligand binding to AR and subsequent activation. Although this approach has initial responses the majority of men relapse with castrate resistant prostate cancer (CRPC) and this is the cause of significant morbidity and mortality. To overcome this and to improve patients treatment options the mechanisms of castrate resistance need to be addressed.

The PI3K/Akt cascade regulates several cellular processes such as proliferation and apoptosis. Akt activation results in phosphorylation of multiple substrates and has been implicated in prostate carcinogenesis and castration resistance. Research has suggested that Akt interacts with signalling cascades implemented in carcinogenesis, in particular the NFkB cascade and AR signalling. The current study investigated the hypothesis that the expression and activation of PI3K/Akt cascade influences the progression to castrate resistant disease using clinical prostate cancer tumours. Fluorescent insitu hybridisation and Immunohistochemistry revealed that PTEN deletion was a common event in castrate resistant prostate cancer and low PTEN protein expression was significantly associated with a poor outcome. PTEN negatively regulates PI3K signalling. Consequently increased levels of PI3K and activated Akt (pAkt ser 308 and pAkt ser 473) were significantly associated with a shorter time to biochemical relapse and shorter disease specific survival. Inhibition of PI3K resulted in a significant reduction in cellular proliferation and Akt phosphorylation. The downstream affects of Akt activation were investigated. Akt has been reported to activate the NFkB signalling cascade both directly and indirectly.

Having shown a significant link between expression and activation of the PI3K cascade and progression to castrate resistant disease, the interaction between Akt and the AR was investigated in both clinical prostate tumours and cell lines. The phosphorylation of AR at the Akt consensus site serine 213 (pARser213) was significantly associated with disease progression. Patients with high expression pARser213 had a significantly shorter time to death from relapse and disease specific survival. Additionally 42% of patients displayed an increase in pARser213 expression, these patients also had a significantly shorter time to death from relapse and disease specific survival. Inhibition of PI3K resulted in a reduction of pARser213 expression in both cell lines. This research highlights the impact of both the PI3K/Akt and NFkB signallingcascades on prostate cancer progression and development of castrate resistant disease. In particular this study highlights the impact of Akt phosphorylation in castrate resistant prostate cancer patients. Therefore phosphorylation of AR at serine 213 may serve as a diagnostic tool to predict patient outcome in response to maximum androgen blockade and inhibition of AR 213 phosphorylation via the Akt cascade may be an effective therapeutic avenue to investigate for treatment of prostate cancer. In conclusion inhibition of the PI3K pathway can lead to cancer cell death and therefore has promising therapeutic potential. Inhibition of the PI3K pathway with natural molecules such as salvestrol Q40 and wortmanin has been demonstrated to lead directly to programmed cell death (i.e. apoptosis) of cancer cells leading to regression of primary tumours and metastases in cancer patients. In some cases complete resolution of bone metastases have been reported with these agents.

BEZ-235 Zytiga Combo

BEZ-235 is a potent inhibitor of PI3K and mTOR which are involved in drug resistance. Continued AR signalling in prostate cancer is mediated by the PI3K/Akt/mTOR pathway and so inhibition of members of this pathway interferes with cell survival signalling and inhibitors of PI3K such as salvestrols causes tumours to undergo apoptosis and cell death. Zytiga resistance is believed to be mediated by PI3K signalling and various inhibitors of this pathway are under investigation in combination with Zytiga. The combination of BEZ-235 with Zytiga is being clinically trialed and should overcome drug resistance and may offer additional anticancer activity.

Molecular structure of BEZ-235 shows it is an imidazoquinoline.

OGX-427 Zytiga Combo

OGX-427 is an antisense oligonucleotide that inhibits HSP-27 production and this new drug is being trialed in combination with Zytiga. Antisense oligonucleotides are space age technology that directly silence specific regions of DNA. In this way the technology can in principle be applied to silencing any protein of choice. This drug targets inhibition of production of HSP-27 a chaperone protein involved in the function of other important kinase enzymes involved in tumour cell proliferation. However there are many unanswered questions with regards to the antisense oligonucleotide approach in general, such as its efficacy and toxicity. Moreover the benefits of HSP-27 inhibition in the treatment of cancer have not been proven and the results of this clinical trial will be interesting.

USA Leads the Way in Prostate Cancer Therapy With Zytiga

The USA leads the way in using cutting edge drugs in clinical practise and Zytiga is now beeing used in 48% of prostate cancer patients in the USA who have progressed following chemotherapy. The use of Zytiga before chemotherapy is less frequent since it has not yet been FDA approved in this scenario. Zytiga has a lot of advantages over other options such as chemotherapy and its approval before chemotherapy by the FDA is being fast tracked with an announcement expected in December.

The abiraterone.blogspot website was set up to give as much information as possible to prostate cancer sufferers about abiraterone acetate (Zytiga) which is a promising new treatment for prostate cancer. This blog also strives to give up to the minute information on other new treatment options for prostate cancer and information on new drugs as they emerge. Regular updates on feeback from patients taking Zytiga are included together with news on new Zytiga combinations with promising potential. This information has been most widely viewed in the USA and the UK with viewers also coming from India and the Ukraine.

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Jevtana Vs Zytiga

Both Jevtana and Zytiga are licensed for use following Docetaxel chemotherapy so what does each have to offer ?

Jevtana is another form of chemotherapy and is a taxane similar to Docetaxel. Jevtana has all the side effects of chemotherapy including liver and kidney damage as well as toxicity to white blood cells causing immunosuppression. Clinical trials showed that Jevtana treatment extended life by only 2.4 months.

Jevatana (Cabazitaxel) is given as an injected infusion every three weeks in a cycle of 3 rounds of chemotherapy. Its cost is around £ 8,000 per infusion and it is not yet approved by NICE for use on the UK NHS.

Zytiga is a form of hormonal therapy that does not suffer from the side effects of chemotherapy and this is why it is the preffered treatment over Jevtana. Zytiga is taken as an oral tablet once daily and is able to work against advanced metastatic disease for which it is FDA apporved. Zytiga is also approved for use on the NHS in the UK.

Stelara Shines in Trials

Stelara the new treatment for Psoriasis has succesfully completed clinical trials and has now been licensed and FDA approved for the treatment of acute psoriasis. Stelara is a monoclonal antibody therapy which is given as a monthly 45 mg subcutaneous injection. The ACCEPT clinical trials showed that Stelara (aka Ustekinumab) effectively treated psoriasis with minimal side effects. Stelara has been designed as a very selective form of therapy specifically targetting IL-12 which is involved in psoriasis plaque formation. By selectively targetting IL-12 Stelara is able to exert its effects aginst psoriasis withou causing any other side effects.

Stelara, Zytiga, and Xarelto are 3 new bockbuster drugs from health giant Johnson & Johnson who know a good drug when they see one, and have selected key drugs in there respective clinical settings. Stelara has unique activity against psoriasis, Zytiga is highly effective against advanced prostate cancer, and Xarelto is an effective anticoagulant used to prevent strokes.

Xarelto Receives FDA Approval

Xarelto the new potential blockbuster by Zytiga manufaturers Johnson & Johnson has received FDA approval for treating variuos types of heart disease and cardiovascular disorders. These include treatment and prohylaxis of AtrialFibrillation, Stroke, and Deep Vein Thrombosis (DVT). Xarelto is the trade name of the powerful anticoagulant agent Rivaroxaban which is an inhibitor of blood clotting factor X alpha. It has powerful anticoagulant effects and prevents blood clots from forming. It is effective at a very low dose of only 10 mg daily taken orally so it is a very convenient and effective means for preventing conditions where blood clots cause problems such as stroke and deep vein thrombosis.

Johnson & Johnson really are on to two winners here producing both Zytiga and Xarelto. It may be that some people need to take both Zytiga and Xarelto together for example patients with advanced metastatic prostate cancer that are also suffering form atrial fibrillation or are at risk of stroke. So these medications may well be used in the same patient populations and these 2 drugs should work well together. The best timing would be to take the Zytiga dose first thing in the morning with 5 mg prednsione, and then 4 hours later to take 10 mg of the Xarelto and the other 5 mg of prednisone. This way there will be minimal pharmacological reactions between the 2 drugs. Both drugs are cleared from the body by the enzyme CYP3A4 and so will compete for this enzyme which will extend the half lives of both these compounds. By offsetting the dosing schedule the competition for CYP3A4 will be reduced and both drugs metabolised safely.

Zytiga Required Before Xtandi Insurance Cover

Insurance companies in the US are only covering Xtandi for use after Zytiga therapy has failed. This clause for the use of Xtandi requires prior use of Zytiga and have clinically progressed on this treatment. Only then will the insurance companies cover the use of Xtandi. This is probably because Xtandi costs $7,500 per month which is considerably more than Zytiga at $5,000 per month.

However there is no clinicall evidence so far that Xtandi works in Zytiga relapsed patients. Patients who have Zytiga Resistant Prostate Cancer (ZRPC) have tumours that have become completely hormone independent so they are unlikely to respond to another antihormonal therapy such as Xtandi. Zytiga has been shown to work when Xtandi has failed but there is currently no evidence that Xtandi will work when Zytiga has failed.

The trial of the closely related antiandrogen AR-509 shows hope that Xtandi may show reponses after Zytiga, since AR-509 is a closely related analogue of Xtandi, and the clinical trials on AR-509 showed a 10% response rate in prostate cancer patients who had previously received Zytiga. So there is hope that at least some patients may benefit from Xtandi post Zytiga.

Cigarette Smoking Protects Against Side Effects of Chemotherapy

Surprising new research results are showing that cigarette smokers suffer less from the side effects of chemotherapy than non-smokers. This is the first time that cigarette smoking has been shown to have positive health benefits. In particular cigarette smokers suffered less damage to the important white blood cellls. This was reflected in a decreased incidence of neutropenia among cigarette smokers. Importantly the white blood cell count (WBC) remained good in the smokers.

The reason for this effect may be due to modulation of the nicotinoid receptors ro could be due to the fact that cigarette smokers are accustomed to having toxic compounds in the body which renders them less susceptible of the toxic effects of the chemotherapy.

Maybe the effects of smoking marijuana should also be investigated on alleviating other side effects of chemotherapy in addition to its use in relieving pain as a narcotic and medical marijuana oil extracted from cannabis indica and cannabis sativa has shown remarkable anticancer properties in its own right due to the THC and CBD acting at the cannabinoid receptors. Smoking cannabis with tobacco will modulate both the cannabinoid and nicotinamide receptors and should work together to alleviate the side effects of chemotherapy.

The research results are summarised below:

Smoking Protects Against Side Effects of Chemotherapy

Purpose:
Compounds in cigarette smoke are known to interact with the metabolism of several anticancer drugs. They may also affect the incidence and severity of adverse events and the efficacy of chemotherapy. The main objective of this study was to examine the effects of smoking tobacco on the pharmacokinetics and toxicities of patients treated with the chemotherapy agents docetaxel (Taxotere) or paclitaxel (Taxol).

Experimental Design:
Smoking status, toxicity profiles, and pharmacokinetic parameters were determined in 566 patients (429 nonsmokers and 137 smokers) treated with docetaxel or paclitaxel.

Results:
Smokers treated with docetaxel showed significantly less grade IV neutropenia (35% vs. 52%) than nonsmokers. Smokers treated with paclitaxel had less grade III–IV leukopenia than nonsmokers (12% vs. 25%), and the white blood cell count (WBC) nadir was lower in nonsmokers (median, 2.7 x 10⁹/L; range, 0.05 x 10⁹ to 11.6 x 10⁹/L) than in smokers (median, 3.3 x 10⁹/L; range 0.8 x 10⁹ to 10.2 x 10⁹/L). Of interest, significantly lower WBC counts and absolute neutrophil counts at baseline were seen in nonsmoking patients treated with paclitaxel (P = 0.0001). Pharmacokinetic parameters were similar in smokers and nonsmokers for both taxanes.

Conclusion:
Cigarette smoking does not hinder the action of docetaxel and paclitaxel. Cigarette smokers treated with the chemotherapy agents docetaxel and paclitaxel had significantly less side effects of neutropenia and leukopenia, and further research is warranted to elucidate this potential protective effect.

Zytiga Inventor Receives Award from Canada

The inventor of Zytiga Professor Gerry Potter has received an award from Canadian cancer diagnostics company CARE Biotechnologies. Zytiga is now approved by Health Canada and is now available in Canadian pharmacies. It is licensed for post chemotherapy use after the drug docetaxel has failed. Professor Potter said on receiving the award "It is so frustarting that Zytiga is not licensed before chemotherapy afterall it is a far safer drug and should be used before chemotherapy is even thought of. Chemotherapy should be alast ditch event after Zytiga has failed not the other way round. Its about time that the FDA approved Zytiga before chemotherapy so that many more men can benefit from this treatment. I designed this drug to replace chemotherapy which is an outdated form of cancer treatment that causes serious side effects. Docetaxel is toxic to the liver, kidneys, and white blood cells so causes severe immunosuppresion. This is not good depleting the cancer patients immune system destrying the very cells that help in cancer recovery. So it really is a nonsense using those sorts of chemotherapy and its about time we abandoned that approach completely. Zytiga makes chemotherapy obsolete and so of course it should really be used as a first line therapy. I'm very please this drug is now benefiting prostate cancer patients in Canada"

Professsor Dan Burke made the award on behalf of CARE biotech, a company specialising in proteomic approaches to early cancer detection that resulted as a spin out from Professor Potter's research on the CYP1B1 and CYP17 enzymes.

www.IJOPT.org

Zytiga Makes Lupron Redundant

Clinical trials are ongoing to evaluate the effects of Zytiga as first line therapy when given 3 weekely Lupron injections as well. Lupron is an LHRH agonist which lowers testosterone levels, whilst Zytiga is able to completely block testosterone production throughout the body, which makes the use of Lupron redundant. So Zytiga blocks all testosterone production anyway and the hormone injection is superfluous. Why do these doctors continue to inject hormones when they know that they are doing nothing more to control the disease. Surely the continued use of Lupron whilst on Zytiga is questionable and there is no evidence that continued use of Lupron with Zytiga is beneficial to the patient. The best neoadjuvant use of Zytiga is therefore as a single agent without Lupron perhaps combined with a low dose of a corticosteroid such as prednisone to offset hyopkalemic side effects.

Xgeva Zytiga Combo

Denosumab (Xgeva) is an antibody injection that targets the RANK ligand and has shown to be effective against bone metastases. Xgeva is now licensed for treating metastatic cancer and Zytiga is licensed for treating metastatic prostate cancer so the combination of these 2 approaches can now be clinically evaluated. The 2 are compatible since Zytiga is taken once daily orally and Xgeva is given as a monthly injection. Combining Xgeva with Zytiga respresents a logical approach to treating metastatic prostate cancer and the results of using this combination in clinical practise will be interesting.

AMG 386 Zytiga Combo

AMG 386 is a new antibody injection that targets a protein involved in blood vessel formation to the tumours. Disrupting this blood supply causes the tumours to die off. Zytiga is now a new standard of care for prostate cancer therapy and so other promising agents are being trialed in combination with Zytiga. Combining AMG 386 with Zytiga offers a multitargetted approach which should have a powerful combined effect and this combination is now under clinical investigation.

AMG 386 has already demonstrated its efficacy against ovarian cancer and its effects against prostate cancer will be very interesting.

AMG 386 is a first-in-class investigational “peptibody” (i.e., a combination of a peptide + an antibody) that is designed to block angiogenesis by inhibiting angiopoietin-1 and -2 (Ang1 & Ang2). Angiopoietins interact with the Tie2 receptor, which mediates vascular remodeling. Ang1 and Ang2 are thought to play roles in angiogenesis, and the maturation of blood vessels appears to be controlled by their precise balance.
Associate Professor of Medicine at Monash University in Australia, Gary Richardson, presented data from phase 2 clinical trials against ovarian cancer showing that AMG 386 in combination with paclitaxel not only extends survival, but is well tolerated and reduces the risk of serious complications.
“Currently the prognosis for ovarian cancer patients is poor,” Professor Richardson said. “Over 75% of patients diagnosed with ovarian cancer present with advanced disease. Current treatments will cure only about a quarter of these patients.”
“The phase 2 trials show that AMG 386 combined with paclitaxel extends survival of heavily pre-treated patients by almost two thirds (4.6 to 7.2 months). In practical terms, this does not add significantly to survival time for terminal patients, but importantly indicates real potential as a first line treatment immediately following surgery.”
Professor Richardson said the treatment worked by inhibiting angiogenesis, the process by which new blood vessels grow from existing blood vessels. “By starving the cancer cells of blood supply, they will die in greater numbers. This form of therapy is complementary to current chemotherapy treatment as it uses a different mechanism to target the cancer.”

Zytiga Receives Award From German Urologists

Zytiga has received an award from the German Society of Urologists for being the most innovative product in oncology for 2012. Zytiga beat competitors Cialis and Xgeva to be recognised as the most significant development in the treatment of prostate cancer as judged by the urologists. The "Innovative Product 2012" (Das Inovativ Produkt 2012) award was presented to Gerd Czekalla of Jannsen-Cilag who received the award on behalf of the company which is the European branch of Johnson & Johnson who manufacture Zytiga.

http://www.youtube.com/watch?v=rL40cfdiyS4

Could Zytiga be Used for Colon Cancer ?

Exciting new research results are revealing a crucial role of testosterone in the development and progression of colon cancer. Colorectal cancer is on the increase in the western world and is often fatal. Surgery leads to debiltating side effects such as the use of colostomy bags and so an effective treatment for colon cancer is really needed. Zytiga effectively blocks testosterone biosynthesis and reduces plasma testosterone level to zero. Could Zytiga be therefore used to treat colon cancer by starving the colon cancer cells of testosterone ? This is an interesting proposition and is worthy of a clinical trial. Perhaps Johnson & Johnson should now investigate this intriguing possibility. A clinical trial of Zytiga against colon cancer would be really interesting scientifically.

Exclusive Interview with Prof Potter the Creator of Zytiga

Dr Hembury caught up with Professor Potter the Creator of the new prostate cancer drug Zytiga at the complimentary and alternative medicine CAM conference in London this weekend and managed to record an exclusive interview which shows amazing insights into the search for a cure for cancer that has led to the discoveries of Zytiga, Idoxifene, Stilserene and Salvestrols.

Dr Hembury: You must be absolutely delighted that Zytiga is now a blockbuster drug.

Prof Potter: Yes this is fantastic news at last I might get something out of it. I've waited 22 years for this. I'm set to receive royalties from the sales of Zytiga so it will be nice at long last to actually receive some financial reward for discovering this important anticancer agent. I knew when I first discovered Zytiga that it would one day become a blockbuster. The results were so good it couldn't fail. Extreme Potency. No toxicity. Very well tolerated so you cant go wrong. What more do you want, this is the perfect cure for Prostate Cancer. What has been frustrating is the length of time that it takes to develop a new drug. I discovered Zytiga 22 years ago almost to this day on the 1 st of November 1990 and here we are in 2012 and only in June this year was it approved for use in NHS hospital in the UK where it was discovered. It is ironic that it has taken US dollars and American Corporate backing to be sold back to the UK at an enormous premium. This could have been taken straight out of my lab in the Institute of Cancer Research within the Royal Marsden Hospital and given to the patients in the Hospital 20 years ago if we didnt live in such a crazy screwed up corporate society.

.....tbc

How Long Does Zytiga Work ?

The question of how long does Zytiga work comes up frequently on traffic sources for this website so I thought I would do my best to answer this.

First it is important to realise that trials showed that 80 % of patients responded to treatment with Abiraterone Acetate (Zytiga). This means that for 20 % of prostate cancer patients Zytiga simply does not work. So in reality for 20 % of patients (i.e. 1 in 5) Zytiga will not work at all.

For the majority that do respond (i.e. 4 out of 5) the reponses can vary enormously. Some men respond dramatically and feel better within a few days with PSA levels declining fast. Other men see a sharp PSA increase for a few months before the levels eventually decline. Others see a slow but steady decline in PSA levels.

20 % of patients show a very good response to Zytiga
20% show a medium response
20% show an initial rise in PSA before it declines
20% show a slow response

The duration of the response also varies from around 6 months up to 6 years. The average response duration from the Phase III clinical trials was 1 year.

i.e. the answer to the question is

On average Zytiga works for 1 year.

When used earlier in the treatment of prostate cancer before chemotherapy the trials showed that Zytiga worked for an average of 2 years.

If used before chemotherapy Zytiga works for 2 years.


The longest Zytiga survivor is 8 years from the Phase I clinical trials in 2004.

There are several 6 year survivors still taking Zytiga from the Phase II clinical trials.

There are hundreds of 4 year survivors on Zytiga from the 1000 cohort of the Phase III trials.

I hope this helps you to understand the soughts of responses that you get with Zytiga, Jez

Zytiga is a Blockbuster Drug

Zytiga the new drug for prostate cancer has now reached blockbuster status surpassing the billion dollar annual sales rate. Johnson & Johnson third quarter sales of Zytiga have now broken through the $ 250 M barrier reaching $ 265 M for this last quarter of a year.

These are remarkable sales figures that have been reached in a short space of time since the drug was only FDA approved in April last year. The rapid uptake of Zytiga reflects the medical oncologists confidence in its efficacy and safety profile. The drug is very well tolerated and the responses in many cases are phenomenal.

Over half the sales were accounted for from the United States alone and European sales are set to increase yet further. Zytiga is now on the national formulary in many European countries and has been approved for prescription use on the NHS in the UK which paves the way for more widespread usage.

Cabozantinib Effective Against Bone Mets

Cabozantinib is a VEGFR inhibitor that prevents blood supply to the tumour and combats bone metastases. Clinical trials have now shown that a low dose of 40 mg of Cabozantinib is still effective in combatting metastatic prostate cancer.

The ultimate combination of Cabozantinib with Zytiga offers a powerful approach to the treatment of metastatic prostate cancer.

Results have been released from a clinical trial of 51 patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases receiving a 40 mg daily dose of cabozantinib (XL-184). The data suggests that the 40 mg daily dose has similar clinical activity to the 100 mg daily dose previously reported from this trial. The key parameters used included measurement of reduction of metastatic bone disease and soft tissue disease, and reduction of bone-related pain and narcotic use, with apparent improvement in adverse event rates and tolerability at the lower dose.

Professor Johann de Bono, M.D., Ph.D., leader of the prostate cancer targeted therapy team at The Institute of Cancer Research, London, and honorary consultant at The Royal Marsden Hospital presented the data today in an oral presentation session on prostate cancer at the European Society for Medical Oncology (ESMO) 2012 Annual Meeting in Vienna, Austria.

"The results presented today at ESMO are consistent with interim data previously reported for the 40 mg cohort of an ongoing investigator-sponsored trial evaluating low-dose cabozantinib in men with CRPC and bone metastases," said Dr Michael Morrissey, Ph.D., president and chief executive officer of Exelixis. "The data suggest that the 40 mg daily dose has activity with respect to a number of key metrics, including bone and soft tissue responses, as well as changes in pain scores and narcotic use. Additionally, the 40 mg daily dose appears to be well-tolerated in patients with metastatic CRPC."

The interim results reported today include data from 51 men enrolled in the 40 mg cohort of an ongoing phase 2 randomized trial. All patients had bone metastases on bone scan and 41% had measurable soft tissue disease. All patients had received prior docetaxel, 67% had received prior abiraterone or enzalutamide (MDV3100), and 25% had received prior cabazitaxel. Seventy-one percent of patients had received at least 2 prior lines of therapy for CRPC. Bone Scan Response (BSR). Computer-assisted evaluation of bone scan lesion area (BSLA) was performed and response evaluated by an Independent Radiology Committee (IRC). An overall BSR rate of 49% was observed, with another 29% of patients having stable disease, and 14% having a best response of progressive disease.

Initial results from ongoing efforts focused on documenting the direct impact of cabozantinib on tumor lesions in the bone of prostate cancer patients were presented, and suggest that cabozantinib's effects on bone scan may be linked to induction of tumor necrosis in bone metastases. In a patient with complete resolution of pelvic metastatic lesions on bone scan, diffusion-weighted magnetic resonance imaging (MRI) findings were consistent with tumor necrosis occurring within the bone metastases. Additional evidence for the tumor selective effect of cabozantinib on bone scans was also presented, based on an analysis of a patient with concurrent osteoarthritis. In this patient, near complete resolution of bone scan tracer uptake at sites of metastatic tumor lesions was observed, while bone scan tracer uptake was maintained at sites of osteoarthritis. To gain further insights into the effects of cabozantinib on bone lesions, there are other ongoing clinical trials using MRI, other imaging techniques, and bone-metastatic tumor biopsies.
Soft Tissue Response. Twenty-one patients had measurable soft tissue or visceral lesions at baseline and 19 patients had at least one post-baseline assessment. Evidence of tumor regression was seen in 79% of the 19 patients with at least one post-baseline assessment. Overall response by RECIST among 21 patients with at least baseline data was partial response in 10%, stable disease in 71%, and progressive disease in 10%. Soft tissue responses were independent of prior therapy.

Tasquinimod Looks Promising in Trials

Tasquinimod is a small molecule with anti angiogenic activity that interupts blood vessel formation in tumours and cuts off their blood supply. Current Phase 2 clinical trials look promising and demonstrate that Tasquinimod has significant anticancer activity and showed antimetastatic activity. Tasquinimod is active at very low doses and a dose of 1 mg daily was the maximum used in the trials. It has dose limiting toxcity above 1 mg daily so this is the maximum that can be safely used.

Molecular structure of Tasquinimod which is a quinoline carboxamide.

Tasquinimod is an analogue of the drug Roquinimex also known as Linomide. Roquinimex has immunostimulant actvity as well as anti angiogenic activity. It also inhibits TNF alpha production. It is deactivated by metabolic 4-hydroxylation, a process that is blocked by a trifluoromethyl group in Tasquinimod.

Molecular Structure of Roquinimex

The precise mechanism of action of Tasquinimod is not known but it does have anti angiogenic activity and stops the development of new vasculature to the tumours.

Tasquinimod  phase II clinical trial  in men with minimally symptomatic metastatic castrate-resistant prostate cancer. A randomized, double-blind, placebo-controlled phase II trial  was conducted in men assigned (at a ratio of two to one) to either oral once-daily tasquinimod (TASQ) 0.25 mg/d escalating to 1.0 mg/d over 4 weeks or placebo. The primary end point was the proportion of patients without disease progression at 6 months, or pain criteria, excluding prostate-specific antigen. Two hundred one men (134 assigned to TASQ; 67 to placebo) were evaluable, and baseline characteristics were well balanced. Six-month progression-free proportions for TASQ and placebo groups were 69% and 37%, respectively, and median progression-free survival (PFS) was 7.6 versus 3.3 months. TASQ significantly slowed progression and improved PFS in patients with metastatic CRPC with an acceptable AE profile.

Docetaxel Therapy for Prostate Cancer

Docetaxel is a type of chemotherapy otherwise known as Taxotere. It is a derivative of Taxol (Paclitaxel) that has improved activity and is widely used in the treatment of advanced prostate cancer. Docetaxel is usually given in combination with prednisone which helps aleviate side effects.

The molecular structure of Docetaxel is shown below and it is an ester of Phenylpropanoic acid and Baccatinol. The raw material for the synthesis of Docetaxel is Baccatin which comes from the Yew tree needles.

Since Docetaxel is a form of chemotherapy it comes with all the side effects of chemotherapy such as nausea, hair loss, liver toxicity, etc so compared to Docetaxel, Zytiga has few side effects.

Zytiga represents the logical choice in patients that have relapsed on current androgen deprivation strategies since it can achieve total androgen blockade. Docetaxel should be seen as the second choice when Zytiga therapy has failed.

When both Zytiga and Docetaxel have failed then Jevtana (Cabazitaxel) can be considered which is a newer version of Docetaxel. It has been shown to have activity in post Docetaxel treated patients.

Molecular structure of the steroidal compound Abiraterone the key ingredient of Zytiga.

Fate of Zytiga in the Human Body

What is the fate of Zytiga when it enters the human body ? How is it processed by the human enzymes ? This all depends on metabolism and the drug metabolism of Zytiga has been thoroughly investigated. This takes place as part of the overall ADME process involving Absorption, Distribution, Metabolism, and Excretion.

For Zytiga (Abiraterone Acetate) only about 5 % is absorbed by the intestine in an unfed state. This means that for a 1000 mg (4 tablet) dose only about 50 mg is being absorbed. The absorption of Zytiga greatly increases when taken with food and a single tablet dose of 250 mg taken shortly after eating results in the absorption of 60 mg of drug which is higher than the full dose taken on an empty stomach.

Absorption of Zytiga

Zytiga as Abiraterone Acetate is taken orally and enters the stomach where it is solubalised by bile acids which are released after eating a meal. The Zytiga tablets disintegrate in the stomach and the released Abiraterone Acetate passes along the small intestine where it is absorbed across the intestinal wall and enters the bloodstream.

Cleavage by Plasma Esterases

The intestinal bloodstream passes through the liver where Abiraterone Acetate escapes first pass metabolism and enters the bloodstream to the rest of the body. In the bloodstream plasma esterases cleave Abiraterone Acetate which is an ester to liberate free Abiraterone.

Binding of Abiraterone to CYP17

The free Abiraterone is then delivered by the bloodstream to the organs of the body including the prostate, the gonads, and the adrenal glands. Here Abiraterone binds tightly to the enzyme CYP17 preventing it from working. This enzyme CYP17 is responsible for making all of the androgens in the human body and so inhibiting CYP17 with Abiraterone causes all androgen production to stop and testosterone levels reduce to zero. This starves the prostate tumours of testosterone and they cease multiplying and start regressing.

Metabolism of Abiraterone by CYP3A4

CYP3A4 makes the inactive metabolite Abiraterone N-oxide. With its pyridyl nitrogen oxidised to the N-oxide Abiraterone is unable to block CYP17 and is rendered inactive.

Metabolsim of Abiraterone N-oxide by SULT2A1

The steroid sulfatase enzyme SULT2A1 puts a sulfate group onto the 3-hydroxy group of Abiraterone N-oxide to make the water soluble Abiraterone N-Oxide Sulfate which is excreted in the urine. About 4 % of Zytiga ends up in this way as the fully metabolised Abiraterone N-oxide Sulfate.

So the Zytiga that enters the human body is processed in a very precise way that allows Zytiga sufficient time to work and yet clears the drug safely from the system.

Molecular Structur of Abiraterone

Dasatinib Zytiga Combo

Dasatinib (Sprycel) is an inhibitor of the Src tyrosine kinase. This enzyme mediates signal transduction from the growth factor receptors to the downstream MAP kinase cascade. Blocking Src stops the meassage to grow that is sent from the growth factor to the cell nucleus. So the nuclear signals to grow are blocked by a Src inhibitor and this should have synergistic effects with total androgen ablation obtained with Zytiga.

The combination of Dasatinib and Zytiga represents a logical combination in the treatment of advanced prostate cancer and is currently undergoing clinical trials to test its safety and efficacy.

Molecular Structure of Dasatinib (Sprycel)

Molecular Structure of Abiraterone (Zytiga)

This looks like a good combination of drugs and we look forward to the results of the clinical trials.

Sunitinib Zytiga Combo

Sunitinib (Sutent) is a combined PDGFR and VEGFR inhibitor that is undergoing clinical trials in combination with Zytiga and Prednisone. VEGFR is inolved in metastatic tumour growth and so an inhibitor of this enzyme will be useful in stopping the spread of the cancer and reducing the growth of existing metastases.

Other VEGFR inhibitors that could be combined with Zytiga are:

Cabozantinib (Exelexis) VEGFR2 & Met Kinase

Sorafenib (Nexavar) VEGFR, PDGFR, Raf Kinase

Regorafenib (Stivarga) VEGFR, PDGFR, B-Raf

Vandetanib (Caprelsa, Astra Zeneca) VEGFR, EGFR, Ret Kinase

Cediranib (Recentin, Astra Zeneca) VEGFR

Pazopanib (Votrient, GSK) VEGFR, PDGFR, c-Kit Kinase

Linifanib (Abbot) VEGFR, PDGFR

Tivozanib (AV-951) VEGFR

Dovitinib (TKI-258) VEGFR, FGFR, c-Kit

Axitinib (Inlyta, Pfizer) VEGFR