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.