EMA Approves Zytiga Pre Chemo

The European Medicines Agency (EMA) has approved the use of Zytiga before chemotherapy throughout the EU including all member states. This follows shortly after the FDA approval of Zytiga pre chemo.

Just before Christmas the EMA advisory committee on new medications for human use made a recommendation to the EMA to approve Zytiga for use before chemotherapy which has now resulted in its European approval. This means that Zytiga is now available earlier in the key member states of France, Spain, Italy, Germany, Ireland and the UK.

Johnson & Johnson's (JNJ) Janssen-Cilag International announced it has received approval from the European Commission today that allows its cancer treatment Zytiga to be adopted in all of the European Union earlier in the treatment process.

The approved broader indication for this oral medication can now be used in combination with prednisone for the treatment of metastatic castration resistant prostate cancer (mCRPC) in men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy but before chemotherapy.

Until now, Zytiga with prednisone has only been approved to treat men with mCRPC whose disease has progressed on or after a docetaxel-based chemotherapy regimen.

Zytiga was discovered by Prof Gerry Potter in the UK at the ICR research labs of the Royal Marsden Hospital. "This EU approval means that Abiraterone is now approved in the UK for use before chemo. This was the intended design strategy to create a drug that replaces chemotherapy so this is very good news" Prof Potter said. 

Jane Griffiths, company group chairman for Janssen Europe said. "This decision by the European Commission is hugely welcomed news. Treating men with Zytiga before they undergo chemotherapy has been shown to improve outcomes in many patients, both in terms of extending survival and in bettering quality of life."

mCRPC occurs when cancer has spread beyond the prostate to other parts of the body and the disease progresses despite serum testosterone below castrate levels.

According to Janssen, Zytiga is the only approved therapy that inhibits production of androgen, which fuels prostate cancer growth, via inhibiting the CYP17 enzyme complex present at the testes, adrenals and the tumour itself.

Abi Comes Home

Abiraterone Acetate (Zytiga) is now available on NHS prescription in the Royal Marsden Hospital where it was first discovered 22 years ago by Professor Gerry Potter in the adjoining Institute of Cancer Research (ICR) CRC Cancer Drug Development Laboratories. The medicinal chemistry research laboratory relocated from Fulham Road where it was known as the Chester Beatty Laboratories. So to keep up the tradition all new drug molecules emerging from the ICR are given CB numbers. Upon discovery this new pharmaceutical compound (later named Zytiga) was first known by its chemical name 17-(3-Pyridyl)androsta-5,16-dien-3beta-ol, and by its Chester Beatty lab registry number CB-7630. Upon aquisition by BTG CB-7630 was given the name Abiraterone Acetate which was known as "Abi" for short.

BTG licensed Abiraterone Aceate to Cougar Biotechnology who liked the number CB-7630 since it matched their own initials of CB. Cougar Biotech then conducted the key clinical trials COU-AA-301 for use following chemotherapy and later the COU-AA-302 trial of Abiraterone Acetate for use before chemotherapy.

Having secured evidence for the safety and efficacy of Abiraterone Acetate in clinical trials Cougar Biotechnology was taken over by Johnson & Johnson. This company filed for FDA approval which was granted in April 2011 and began marketing the drug as "Zytiga". The european medicines agency EMA followed suit approving Abiraterone Acetate for use after chemotherapy throughout europe in Sept 2011.

In June 2012 the UK regulatory authority NICE recommends Abiraterone Acetate for use on the NHS which allows UK cancer patients to receive the drug free on prescription.

Now at the start of 2013 Abiraterone Acetate (Zytiga) is finally available in the Royal Marsden Hospital for prescription use on the NHS to prostate cancer patients who have failed chemotherapy.

So Abi comes home...

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.