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.