Why Tivozanib Deserves FDA Approval

Tivozanib is a new type of anticancer agent that selectively targets the VEGF receptors and has demonstrated useful clinical activity in Phase 3 trials against kidney cancer. Tivozanib is being developed by AVEO pharmaceuticals in partnership with Astellas, the company that partnered Medivation in the devlopment of Xtandi. What sets Tivozanib apart from other VEGFR inhibitors is that it targets all three isoforms providing complete receptor blockade. Targetting VEGF signalling has already led to successful anticancer therapies such as Avastin.

Since VEGF signalling is involved with the growth and spread of metastases VEGFR inhibitors have potential for treating all types of solid tumours that are prone to metastasis such as lung cancer, breast cancer, and prostate cancer. The potential utility of Tivozanib in treating prostate cancer has been somewhat overlooked and no clinical trials have been started yet, but this drug would make a good combination with Zytiga (i.e. Tivozanib Zytiga Combo) for treating metastatic prostate cancer, since both drugs are well tolerated and would combine well together. The VEGFR-2 inhibitor Cabozantinib in combination with Zytiga is currently in clinical trials and the results against resolution of bone mets look impressive.

Molecular structure of Tivozanib shows that it is a very well designed drug. The quinazoline group mimics adenosine and binds into the ATP binding site of the VEGF receptor with the chloroary side chain fitting into the hydrophobic binding pocket.

The next generation of potential blockbusters in oncology will come from the new "inibs", tyrosine kinase inhibitors that are targetted against specific kinases involved in cancer survival. This new generation of oncology drugs includes Ibrutinib (PCYC), Cabozantinib (EXEL), and Tivozanib (AVEO), all of which are showing exciting clinical activity. The first generation of "inibs" are already blockbusters such as Imatinib otherwise known as Glivec (NVS).

The Phase 3 clinical trials of Tivozanib are against kidney cancer, and compared this drug with the current VEGFR inhibitor Sorafenib. There was no increase in overall survival (OS) with patients treated with Tivozanib compared with Sorafenib, but there was a statistically significant increase in progression free survival (PFS) which was the primary goal of the trial. This trial also demonstrated the safety of Tivozanib which showed that it was a well tolerated drug with few side effects and importantly had an improved safety profile when compared to Sorafenib.

Taken together the improvement in progression free survival and good safety profile of Tivozanib make this a useful agent in oncology for treating kidney cancer and warrants regulatory approval.

10 Top Biotechs Advancing Oncology

There have been recent rapid advancements in the science of oncology with greater understanding of the biology of cancer and new therapeutic targets are being identified which hold the promise of targetted therapy for cancer. Behind the big pharma companies such as J&J and Novartis are the smaller biotech copmanies which are the originators of these new medications. So heres an insiders assessment of the biotechs developing exciting new drugs in oncology which are set to boom in 2013:

No.1 BTG (UK: BTG) - Zytiga (Abiraterone Acetate), licensed to J&J (JNJ)
                                      Varisolve

No. 2 Medivation (MDVN) - Xtandi (Enxalutamide), partnered with Astellas

No. 3 Exelixis (EXEL) - Cometriq (Cabozantinib) FDA approved for thyroid cancer.
                                      Potent anti-metastatic agent, set to be a blockbuster
                                      Clinical trials for prostate, breast, lung, kidney, and brain cancer

No. 4 Pharmacyclics (PCYC) - Ibrutinb for CLL and MCL, partnered with J&J, FDA breakthrough status.

No. 5 Astex (ASTX) - 6 Drugs in clinical trials, partnered Novartis and J&J.

No. 6 Array (ARRY) - 5 Drugs in clinical trials, several partners.

No. 7 Curis (CRIS) - Hedgehog Pathway Inhibitor, partnered Roche.

No.8 Aveo (AVEO) - Tivozanib for kidney cancer, FDA submitted, partnered Astellas.

No. 9 Cleveland Biolabs (CBLI) - Curaxins, apoptosis.

No. 10 Spectrum Pharmaceuticals (SPPI) - Zevalin targetted radiotherapy

Zytiga Superior to Ketoconazole

Zytiga and Ketoconazole are both widely used in prostate cancer therapy and have a common mechanism of action both working by inhibiting the enzyme CYP17 which is responsible for androgen biosynthesis. Inhibiting this enzyme lowers testosterone levels which results in tumour regression. Ketoconazole is a non selective CYP inhibitor developed as an antifungal agent but was also found to inhibit a number of human CYP enzymes including CYP3A4 in the liver and CYP17 in the adrenals and testes. Zytiga is a specially designed inhibitor of CYP17 targetted specifically at this enzyme and is 10,000 times more potent as a CYP17 inhibitor than Ketoconazole.

The two drug have now been compared directly in clinical practice and as expected Zytiga showed superior overall survival results compared with Ketoconazole.

Comparison of Abiraterone Acetate (Zytiga) versus Ketoconazole in patients with metastatic castration-resistant prostate cancer (mCRPC) refractory to Docetaxel.

Background: Zytiga is standard treatment in patients with mCRPC refractory to docetaxel. Zytiga is a potent and selective CYP 17 inhibitor that blocks the synthesis of androgens in the testis, adrenal glands, and prostate tumour cells. However, in some countries where Zytiga has not been approved yet, Ketoconazole is used as an alternative CYP 17 inhibitor. Although preclinical data suggests that Ketoconazole is much less specific and potent as an inhibitor of CYP 17, there is no clinical data comparing both agents. The present study aimed to compare the clinical effectiveness of Zytiga vs Ketoconazole in patients with mCRPC refractory to Docetaxel.

Methods: Records from 156 mCRPC patients treated with Ketoconazole 200 - 400 mg 3x day, in 4 centers across the US were reviewed retrospectively. 26 pts treated post Docetaxel were individually matched by clinicopathologic factors to patients treated with Zytiga. We compared the PSA response (decrease ≥50% from baseline), biochemical (bPFS) and radiological (rPFS) progression free survival, and overall survival (OS) between the groups. Progression free survival and overall survival were determined by Cox regression.

Results: The groups were matched by Gleason score and disease extent (limited-axial skeleton and/or nodal vs extensive- appendicular skeleton and/or visceral). Furthermore, they were balanced regarding median age, PSA response and time to progression on prior Docetaxel.
In the groups of Zytiga vs Ketoconazole,

PSA response was 46% for Zytiga vs 19% for Ketoconazole,

Median biochemical bPFS 7 months for Zytiga vs 2 months for Ketoconazole,

Median radiological rPFS 6 months for Zytiga vs 2.5 months for Ketoconazole,

Median overall survival (OS) 17 months for Zytiga vs 12 months for Ketoconazole

Therefore treatment with Zytiga increases overal survival by an extra 5 months compared to treatment with Ketoconazole.

Conclusions: In mCRPC refractory to Docetaxel chemotherapy, the outcome of patients treated with Zytiga was superior to Ketoconazole.

European Zytiga Sales Increase Whilst US Sales Decline

The latest sales figures for Zytiga show that sales appear to be remaining static going from $ 265 M in Q3 to $ 264 M in Q4, but these figures conceal two opposite trends that are affecting sales:

- A decrease in US sales down from $ 136 M in Q3 to $ 114M in Q4
= reduction of $ 22 M.

- An increase in the rest of the world (ROW) sales from $ 129 M in Q3 to $ 150 M in Q4
= increase of $ 21 M.

The ROW sales increase and US sales decrease cancel out to give no overall increase in Q4 sales.

The ROW sales figures are mainly contributed by an increase in European sales where Zytiga is now available on the National Health Services of a number of European countries such as the UK and Germany.

The decrease in US sales of Zytiga is largely due to competition from the newly licensed rival drug Xtandi. Without the market presence of Xtandi the US sales of Zytiga would have been expected to continue increasing as it has been doing, but this is the first time US Zytiga sales have declined representing market share taken by Xtandi. However this decrease will probably be short lived as Xtandi's shortfalls and lack of efficacy are revealed in clinical practise. There are already some oncologist who have tried Xtandi and are now switching thier patients back to Zytiga.

Further evidence for the impact of Xtandi comes from the fact that Xtandi is only FDA approved for use in the USA and has not yet received European approval which would explain why the European sales figures have been unaffected and continue to grow.

Zytiga Q4 Sales 2012

The latest Q4 2012 sales figures for Zytiga of $264 M have been released today by Johnson & Johnson. The total sales for 2012 reached $ 961 M, just falling short of the billion dollar mark.

The 2012 sales figures for Zytiga are as follows:

Q1    $ 200 M
Q2    $ 232 M
Q3    $ 265 M
Q4    $ 264 M

Total $ 961 M

These figures show a levelling off of Zytiga sales with no significant growth over the last quarter. This may in part be due to the launch of Xtandi following its FDA approval in the post chemotherapy market. Xtandi is a competitor to Zytiga in the post chemotherapy space and some clinicians have opted to try this new treatment.

However Zytiga is now approved for the treatment of prostate cancer before chemotherapy and this is expected to double its market potential and 2013 sales may be as high as $ 2 billion.

Casodex Zytiga Combo

Casodex is a widely used antiandrogen and some oncologists are combining Casodex with Zytiga. This combination has promising potential by using an antiandrogen such as Casodex together with a hormone boisynthesis inhibitor Zytiga.

Zytiga blocks CYP17 and prevents all androgens including testosterone from being made. In the absence of testosterone caused by Zytiga the antiandrogen has a much better chance of working, since there is no testosterone to compete with its own binding to the androgen receptor (AR). So Casodex should bind better to the androgen receptor in the presence of Zytiga and so will inrease its activity as an antiandrogen.

There is also an added bonus of this combination as a result of drug meatbolism. Casodex inhibits the liver enzyme CYP3A4 which is the same enzyme that deactivates Zytiga to its inactive N-oxide metabolite. So Casodex will reduce the metabolism and clearance of Zytiga and increase its half life.

Co-administartion of Casodex with the drug Midazolam, which is a CYP3A4 substrate, showed that this increased the drug concentration 1.5 fold and doubled the half-life. This would be a useful effect when considered in context of the Casodex Zytiga combo. In practise this means that

a) The same dose of Zytiga (1000mg, i.e. 4 x 250 mg tablets) can be used for double the effect.

b) The dose of Zytiga could be reduced to 500mg (i.e. 2 x 250 mg tablets) with an equal effect.

The end result of combining Casodex with Zytiga is therefore to:

1) Increase Casodex antiandrogenic activity.

2) Increase Zytiga effects by 2-fold.

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.

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.