Why is VEGFR Inhibition Important ?

The Vascular Endothelial Growth Factor Receptor (VEGFR) is responsible for providing the blood supply to the tumour. Inhibit VEGFR and the vascularisation to the tumour ceases and the tumour undergoes necrosis and dies off. VEGFR is also responsible for blood supply to the metastatic tumours and inhibitors of VEGFR have antimetastatic effects.

Zytiga is currently undergoing clinical trials to test the efficacy in combination with a VEGFR inhibitor.

2 clinical combinations that are in trials are:

1. Cabozantinib Zytiga Combo

2. Sunitinib Zytiga Combo

Vascular Endothelial Growth Factor Receptor (VEGFR) is the receptor of VEGF the Vascular Endothelial Growth Factor. VEGFR is involved in cell proliferation, migration, survival and permeability. The VEGFs include five known structurally-related mammalian ligands (VEGFA, VEGFB, VEGFC, VEGFD, and placenta growth factor, PLGF) and there are also three structurally related VEGFRs subtypes (VEGFR1, VEGFR2, and VEGFR3). 

Solid tumors require the growth and dissemination of blood vessels and lymphatic vessels to support the metastatic growth of cancers. Following the recognition of growth factor receptor pathways that regulate angiogenesis, a number of small molecular inhibitors and antibodies have been developed that target the activity of vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) pathway. This includes oral small-molecule tyrosine kinase inhibitors currently in clinical practice, namely sunitinib and sorafenib. These are commonly used in the treatment of renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC), two indications that are known to develop resistance to conventional chemotherapeutics.

The VEGFs include five known structurally-related mammalian ligands (VEGFA, VEGFB, VEGFC, VEGFD, and placenta growth factor, PLGF). The VEGFs are disulfide-bonded homodimers, however, VEGFA and PLGF heterodimers are also known to exist. Due to alternative splicing or due to processing, VEGF ligands occur as several different variants. As a result, these variants bind differently to both VEGFRs and to co-receptors resulting in different biological responses including angiogenesis, lymphangiogenesis, permeability, inflammatory cell recruitment and fatty acid uptake. VEGFs are produced by several different cell types and act in a paracrine manner. The VEGFs bind to three structurally related tyrosine kinases (VEGFR1, VEGFR2, and VEGFR3). Modulating the effect of the VEGFRs are a number of co-receptors that lack intrinsic catalytic activity (i.e. heparin sulfate, neurophilins and integrins) and bind to VEGF.^[1]

VEGFR1 (also known as Fms-like tyrosine kinase 1, Flt1, in mice) is a single-transmembrane glycoprotein structurally related to VEGFR2 and VEGFR3. VEGFR1 is expressed at high levels in vascular endothelial cells, and along with VEGFR2 binds to VEGFA. VEGFR1 is noted to bind exclusively to VEGFB and PIGF. Expression of VEGFR1 is noted to occur during vessel growth and remodeling activity. Non-endothelial cells that express VEGFR1 includes monocytes and macrophages, human tropholblasts, renal mesangial cells, vascular smooth muscle cells, dendritic cells and various tumor cells. A key regulator of VEGFR1 gene expression is hypoxia.^[1]

VEGFR2 (also known as KDR; kinase insert domain receptor, in the human and Flk1; fetal liver kinase-1, in mice) binds VEGFA with a 10-fold lower affinity than VEGFR1.  Other targets of VEGFR2 include proteolytically processed VEGFC and VEGFD. The only known ligand to uniquely bind to VEGFR2 is the open reading frame-encoded VEGFE. VEGFR2 is expressed in most adult vascular endothelial cells as well as circulating endothelial progenitor cells, pancreatic duct cells, retinal progenitor cells, megakaryocytes and hematopoietic cells. VEGFR2 expression is induced in conjunction with active angiogenesis (i.e. the uterus during the reproductive cycle) and in pathological process related to neovascularization (i.e. cancer). VEGFR2, often in combination with VEGFR3, is expressed at significantly upregulated levels in the tumor vascular endothelium in most common human solid tumors. Tumor cells can also express VEGFR2, however, epithelial and mesenchymal tumor cells typically express VEGFR1 rather than VEGFR2. Nevertheless, increased expression of VEGFR2  on tumor cells has been noted for melanoma and hematological malignancies. And, there is evidence supporting a relationship between chronic inflammation and tumor development.

 

VEGFR3 (also known as Fms-like tyrosine kinase 4, Flt4 in the mouse) is activated by the binding of VEGFC or VEGFD, once these two ligands undergo proteolytic processing (this increases their affinity to VEGFR2 and VEGFR3). In addition, hVEGFD shows similar affinity to both VEGFR2 and VEGFR3, while mVEGFD binds only to VEGFR3. During embryogenesis, VEGFR3 expression occurs in the primary vascular plexus at day E8.5. In late stages of embryogenesis, VEGFR3 is expressed in venous endothelial cells of the cardinal vein, that results in VEGFR3-expressing lymphatics. Postnatally, VEGFR3 plays an important role in lymphatic endothelial cells, but its expression is also observed in endothelial cells engaged in active angiogenesis, such as tumor vessels, in endothelial tip cells of angiogenic sprouts in the developing retina or in chronic inflammatory wounds. The receptor is also found in non-endothelial cells such as osteoblasts, neuronal progenitors and macrophages – all of which may indirectly support angiogenesis. It remains unclear if tumor cells express VEGFR3. Despite this lack of clarity, inhibiting VEGFR3 activity is associated with the arrest of tumor vascularization, resulting in decreased vascular density in several tumor models.^[1]

Since the VEGF-VEGFR pathway plays a significant role in angiogenesis, and it is widely known that VEGF is highly expressed in tumor and stromal cells, especially in the inflammatory cells of human tumors, 37 drugs that are VEGFR inhibitors are currently undergoing clinical trials for cancer therapy.

^{Drugs that inhibit VEGFR are listed below}

Cediranib (AZD2171)

Sunitinib Malate (Sutent)

Cabozantinib (XL-184)

ENMD-2076

Amuvatinib (MP-470)

AEE788 (NVP-AEE788)

Ponatinib (AP24534)

TG101209

Prednisone - The Unsung Hero of Cancer Therapy

Prednisone is used in combination with many drugs in prostate cancer therapy such as Docetaxel, Mitoxantrone, and Zytiga. It is used to potentiate the anticancer effects of these agents and to decrease side effects. However Prednisone comes with side effects of its own but these are manageable. But it also has anticancer effects of its own and explains the high overall survival of the Zytiga trial placebo arm who were all taking Prednisone plus placebo.

Docetaxel plus Prednisone has become the mainstay of prostate cancer chemotherapy and is now the standard to which other therapies are compared.

Mitoxantrone plus Prednisone is also another chemotherapy treatment option if Docetaxel treatment fails.

Zytiga plus Prednisone is now the Gold Standard of care and has set new standards in the treatment of prostate cancer.

Altogether Prednisone is the unsung hero of all these treatments and is also used for Leukaemia and Lymphoma therapy.

The molecular structure of Prednisone shows that it is a corticosteroid.

Akt Inhibitor Zytiga Combo

Clinical trials are underway on the combination of the Akt inhibitor GDC-0068 in combination with Zytiga and Prednisone. Akt is a downstream target of PI3 Kinase signalling involved in drug resistance and tumour progression. GDC-0068 is an inhibitor of Akt with an IC50 of 5 nM and a 400 mg dose has a half life of 24 hours. Chemotherapy can induce Akt activation in resistant cells and so an Akt inhibitor can overcome resistance to chemotherapy. PI3 Kinase / Akt signalling is involved in Zytiga resistance and so an inhibitor such as GDC-0068 may overcome Zytiga resistance. GDC-0068 is being developed by Genentech Roche and is a selective and potent inhibitor of Akt also known as PKB. Zytiga in combination with Prednisone is now the Standard Of Care in prostate cancer therapy and so many agents are being trialled in combination with these agents. The Zytiga GDC-0068 combo offers a rational approach to overcoming Zytiga resistance and prolonging its duration of action.

Key binding of Abiraterone (Zytiga) with the enzyme CYP17

 Structure of Prednisone (needed to overcome potassium deficiency Hypokalemia side effect of Zytiga)

Structure of Abiraterone (Zytiga)

Reduction of PSA and Tumour Volume by Zytiga

Should Xtandi Be Taken at a Lower Dose ?

The incidence of seizure from Xtandi has increased to 7 patients in the ongoing clinical trials in 800 men at a dose of 160 mg daily. Xtandi has a half life in the human body of 7 days and so its concentration will increase in the body upon daily dosing reaching potentially fatal levels in the body. The level of the drug in the human body increases daily and after 30 days the onset of seizures is observed.

Surely with a half life of 7 days this drug should be taken on a once weekly basis instead of once daily to allow the body time to metabolise it. This would reduce the cost of Xtandi dramaticaly from $ 7,450 per month to around $ 1,000 per month which makes economic sense. Weekly Xtandi dosing takes into account the long half-life of this drug and would prevent drug accumulation and so may circumvent the risk of heart seizure.

Zytiga Inhibits CYP2D6 Metabolism of Dextromethorphan

Zyiga is the trade name for Abiraterone Acetate. Once absorbed by the body this prodrug is cleaved by plasma esterases in the bloodstream to liberate free Abiraterone which inhibits the CYP17 enzyme in tumours to stop all androgen production and switches off testosterone biosynthesis. Abiraterone has been designed as a very potent and selective inhibitor of CYP17 and does not inhibit closely related CYP enzymes such as CYP19 which is used for comparison.

However during clinical development it was found that Abiraterone also inhibited the liver enzyme CYP2D6. This has important implications for drugs that are activated or deactivated by CYP2D6. Dextromethorphan is a substrate for CYP2D6 and its metabolism has been studied clinicaly in the presence of Zytiga which showed an increase in the concentration curve of Dextromethorphan showing that Zytiga decreases the metabolism of this drug and leads to prolonged Dextromethorphan exposure.

Tamoxifen is activated to its 4-hydroxy metabolite 4-hydroxy tamoxifen by CYP2D6 which is thought to be the active antiestrogenic metabolite. Tamoxifen is also N-demthylated by CYP2D6 so this enzyme plays an important role in Tamoxifen metabolism. Zytiga is undergoing clinical trials against advanced breast cancer and so its effects on decreasing CYP2D6 mediated metabolism should be taken into account. The predictions are that Zytiga will inhibit CYP2D6 and decrease the amount of 4-hydroxy tamoxifen formed and therefore Zytiga will decrease the activity of Tamoxifen.

Consequences of CYP3A4 Metabolism of Zytiga

Zytiga is metabolised by the liver enzyme CYP3A4 to an inactive metabolite that is excreted from the body. The usual half life of Zytiga is 12 hours and this rate of drug clearance is goverened by the activity of the CYP3A4 enzyme. Modulators of this enzyme will therefore affect the rate of clearance and hence activity of Zytiga.

There are 2 types of modulators of CYP3A4, inducers and inhibitors.

1. CYP3A4 inducers e.g. Rifampicin, Xtandi (Enzalutamide)

A CYP3A4 inducer will elevate the levels of this enzyme in the liver and increase the metabolism of Zytiga resulting in a shorter half life and reduced drug activity.

A clinical trial is underway to investigate the effect of Rifampicin which is a potent inducer of CYP3A4 on the metabolism of Zytiga (Abiraterone). This will look at the effect of Rifampicin exposure on the effects of a single 1000 mg dose of Zytiga and measure the levels in the plasma and rate of clearance to calculate the half life. The results of this study will have implications on the combined use of Xtandi with Zytiga since Xtandi (Enzalutamide) is also a potent inducer of CYP3A4 and may result in lower activity of Zytiga.

2. CYP3A4 inhibitors e.g. Ketoconazole, Itraconazole.
On the other hand a CYP3A4 inhibitor will block the activity of this enzyme and reduce the metabolism of Zytiga resulting in a longer half life and increased activity due to prolonged drug exposure.

Another clinical trial is investigating the effect of Ketoconazole on the metabolism of Zytiga. In theory since Ketoconazole is an inhibitor of CYP3A4 it should decrease the rate of Zytiga metabolism and prolong its duration of action. This study is investigating the effect of Ketoconazole exposure to a single 1000 mg dose of Zytiga to measure its half life. This could mean that Ketoconazole may be succesfully combined with Zytiga to increase its activity and would mean that lower doses of both drugs could be used together.

Yervoy Zytiga Combo

It had to happen - combine monoclonal antibody therapy with Zytiga antihormonal therapy. Yervoy (Ipilimumab) is a monoclonal antibody aimed at the CTLA-4 antigen which reactivates the Cytotoxic T-Lymphocytes to recognise and destroy tumour cells. Zytiga is now established as a standard of care in prostate cancer therapy and so many new drugs with potential against prostate cancer are now compared with Zytiga therapy.

Yervoy in combination with Zytiga respresents an interesting combination since the Zytiga will starve the tumour of androgenic hormones whilst the Yervoy will stimulate the killer T-Cells to attack the tumour and should work against tumours that have metastasized. A clinical trial is currently underway to test the safety and efficacy of this combination with oral Zytiga being taken daily along with Prednisone, and Yervoy administered IV every 3 weeks for 4 cycles. The effect on PSA response will be examined along with progression free survival time.

Advanced Breast Cancer Responds to Zytiga

The first response to Zytiga in treating advanced breast cancer has been reported in an ongoing clinical trial to evaluate its efficacy. The candidates for this trial had been heavily pretreated with chemotherapy and hormonal therapy. Any response in the category is deemed remarkable. 6 patients were enrolled into the Phase I part of the study. Of these patients there has been one response to Zytiga with an overall survival of 14 months. This is an important result and shows that Zytiga can continue to work when other therapies such as chemotherapy have failed. Zytiga is a rational approach to the treatment of breast cancer since it blocks the production of all androgenic and estrogenic hormones including estradiol. The level of these hormones falls to undetectable levels following Zytiga treatment. This starves the breast cancer of estrogens and they cannot grow any further halting tumour development. This response to Zytiga and the low toxicity profile in combination with hydrocortisone means that Zytiga would work as a safer option to chemotherapy and warrants further investigation in the pre chemotherapy setting for the earlier treatment of breast cancer especially if it is hormone dependent breast cancer.

Zytiga for Breast Cancer

PHASE I/II TRIAL OF ZYTIGA (ABIRATERONE ACETATE, AA) IN ESTROGEN RECEPTOR (ER) OR ANDROGEN RECEPTOR (AR) POSITIVE METASTATIC BREAST CANCER

Background
Abiraterone irreversibly inhibits 17-hydroxylase/c-17-20 lyase (CYP17), reducing androgen and estrogen levels and improves overall survival from castration resistant prostate cancer. We hypothesized that: A) Postmenopausal ERα+ MBC continue to be ERα + /AR driven; and, B) Postmenopausal ERα- AR+ MBC can be driven by AR.

Methods
This Phase I/II trial of AA with hydrocortisone evaluated tolerability, pharmacokinetic (PK)-pharmacodynamic (PD) profile and anti-tumor activity. Two parallel but non-randomized Phase II arms utilized a Gehan design (95% probability of detecting a 24wk clinical benefit rate (CBR, partial response [PR] + stable disease) of > 20%; 14 patients [pts] in the first stage; 11 in the second stage for each arm). Prior therapy with ≥ 2 lines of endocrine therapy (for ERα+ arm); ≥ 1 line of chemo (for AR + ERα- arm); and prior trastuzumab if HER2-positive was required.

Results
In the phase I study, daily dosing of AA was well tolerated with variable PK at all dose levels. PD studies of CYP17 blockade demonstrated suppression of circulating estradiol and androgen levels below the limit of assay detection with 1000mg and 250-2000mg AA respectively; 1000mg was selected for Phase II evaluation. In the ERα+ arm, 6 pts (Phase I) and 25pts (Phase II) received 1000mg AA, of whom 4 were HER2-positive. The median age (range) was 60 (46-80), prior lines of hormonal and chemotherapy were 3 (2-4) and 2 (0-5) respectively. There was 1 partial response (PR) lasting 14m in a pt who had received 4 and 5 lines of hormonal and chemotherapy respectively. Median progression-free survival was 11wk. CBR at 24wk was 21%. In the AR + ERα- arm, recruitment is ongoing. Hypokalaemia easily managed by hydrocortisone administration, was the commonest drug related adverse event (AE).

Conclusion
Zytiga was well tolerated and merits further evaluation in Metastatic Breast Cancer.

VEGFR Inhibitor Zytiga Combo

Targetting VEGFR is an important strategy in combatting tumour growth and metastatic spread. VEGFR stimulates new blood vessel formation to the tumour and allows blood supply to reach metastatic growths. By blocking VEGFR either directly by using a VEGFR inhibitor or indirectly by inhibiting a down stream signalling pathway such as the PI3 Kinase / Akt pathway. In this way a PI3K inhibitor or an Akt inhibitor can be used to block VEGFR mediated signalling. The PI3K / Akt pathway is also involved in the drug resistance mechanism for Zytiga. An inhibitor of PI3K or Akt would stop resistance to Zytiga and greatly prolong its duration of action.

PI3K / Akt pathway inhibitors under investigation in combination with Zytiga and Prednisone.

1. Salvestrol Zytiga Combo. Includes the PI3K inhibitor salvestrol Q40.

2. GDC-0980 Zytiga Combo. PI3K reversible inhibitor.

3. PX-866 Zytiga Combo. PI3K irreversible inhibitor.

4. GDC-0068 Zytiga Combo. Akt reversible inhibitor.

VEGFR Inhibitors in combination with Zytiga will help stop the spread of the cancer and reduce bone mets.

VEGFR Inhibitors under investigation in combination with Zytiga and Prednisone.

1. Cabozantinib Zytiga Combo.

2. Sunitinib Zytiga Combo.

Zytiga Provides Significant Survival Benefit

The final analysis of the COU-301 phase 3 clinical trial on Zytiga shows this drug has significant overall survival benefits. The full results were published in the prestigous scientific journal "Lancet Oncology."

Zytiga had improved overall survival in metastatic castration-resistant prostate cancer at a final analysis of the COU-301 double-blind, placebo-controlled phase III study.

The study had involved 1195 patients at 147 sites in 12 countries. Patients were eligible if they had metastatic castration-resistant prostate cancer progressing after docetaxel. Patients were randomly assigned (ratio 2:1) to receive either abiraterone acetate 1000 mg orally once daily plus prednisone 5 mg orally twice daily (n=797) or placebo plus prednisone (n=398). The primary endpoint was overall survival.

The following results were provided after a median follow-up of 20.2 months:

• Median overall survival (OS) for the Zytiga group was longer than in the placebo group (15.8 months vs. 11.2 months) giving an overall survival benefit of 4.6 months.

• Median time to PSA progression  was 8.5 months in the Zytiga group vs. 6.6 months in the placebo group.

• Median radiological progression-free survival (PFS) was 5.6 months in the Zytiga group vs. 3.6 months in the placebo group.

• The proportion of patients who had a PSA response was greater in the Zytiga group (235 [30%] of 797 patients vs. 22 [5%] of 398.


The researchers concluded that this final analysis shows that abiraterone acetate prolongs overall survival in patients with metastatic castration-resistant prostate cancer who have progressed after docetaxel treatment, whilst no new safety issues were identified with the increased follow up period.

HSP-90 Inhibitor Zytiga Combo

Zytiga has a very good safety profile and so is ideal for combining with other drug therapies. Such combinations may be designed to overcome Zytiga resistance. Many combination therapies are currently under investigation that are rationally targetted against prostate cancer and the signalling pathways involved in drug resistance including the PI3 kinase inhibitor salvestrol zytiga combo. An HSP-90 inhibitor is a good combination with Zytiga since it will have its own anticancer activity and may overcome Zytiga drug resistance. The inhibition of HSP-90 is rational since this is a chaperone protein that is responsible for the stability of other proteins including the androgen receptor (AR).

Clinical trial tests new combination treatment for advanced prostate cancer

Scientists hope to reverse resistance that can develop to the next-generation prostate cancer treatment abiraterone by combining it with a promising experimental treatment, and believe the combination also has potential when given at an earlier stage to prevent resistance developing.

The Institute of Cancer Research, London UK, and its partner The Royal Marsden Hospital will lead an international, multi-centre Phase I/II study to assess the combination of an HSP90 inhibitor called AT13387 with abiraterone. A second stage of the trial will also test AT13387 as a single agent.

Abiraterone was discovered by Professor Gerry Potter whilst at The Institute of Cancer Research (ICR) and this year he was acknowleged with an award from the Royal Society of Chemistry for his key role in devloping this drug. Abiraterone is now marketed as Zytiga by Johnson & Johnson and is now available on the NHS to treat men with advanced prostate cancer who were no longer responding to standard treatments including docetaxel chemotherapy. Abiraterone can extend life for men with advanced cancer by several years but some patients’ tumours ultimately develop resistance.

Professor Potter said "Zytiga is now widely used to treat prostate cancer and is being currently used worldwide in over 10,000 patients. Zytiga resistant prostate cancer is now emerging as a problem in oncology and various strategies are being investigated to overcome Zytiga resistance. The use of an HSP-90 inhibitor in combination with Zytiga makes good sense since this prevents the androgen receptor mediated signalling from functioning. This will make the prostate tumours shrink and the cancer should regress significantly with this combination. It also has the potential of targeting the bone mets which are normally difficult to treat."

HSP90 is a protein found in all human cells that is vital for helping other proteins fold into their correct shape. Cancer cells are especially dependent on HSP90, and so blocking this protein with drugs is considered a promising strategy to treat cancer.

The ICR carried out the important early work that uncovered the potential of targeting HSP90 to treat cancer, including publishing the first detailed 3D image of the protein. Many HSP90-inhibiting drugs are in development globally and being tested in a range of cancer types, including AT13387 from Astex and AUY922, which was discovered at the ICR and is licensed to Novartis.

Trial brings together two important research strands

The new trial, sponsored by Astex, will test the drug AT13387 in combination with abiraterone, following laboratory studies that highlighted the promise of this strategy in men with advanced prostate cancer.

The first part of the new study, Phase I, will include up to 52 patients with castration-resistant prostate cancer who are no longer responding to treatment with abiraterone. They will continue to receive their normal dose of abiraterone and will also be randomly allocated one of two different treatment regimens of AT13387.

If the trial shows the combination is safe and establishes biological effectiveness, the best of the two treatment regimens will be taken into Phase II testing. In this stage, up to 112 patients will be randomly assigned to receive AT13387 either in combination with abiraterone or alone.

Professor Paul Workman, deputy chief executive of the ICR and head of the Cancer Research UK Cancer Therapeutics Unit at the ICR, said: “We are pleased to act as clinical lead on this trial, which for the first time brings together two important strands of research pioneered at the ICR – new-generation anti-hormone treatments and inhibitors of the molecular chaperone HSP90. Our pre-clinical work has shown that combining these two approaches gives a powerful anticancer effect and should reduce the potential for drug resistance to arise. Initially we will be testing the combination in patients who have stopped responding to abiraterone in a bid to renew the drug’s effectiveness, but ultimately we hope that the combination could one day also be used up front to prevent resistance developing.”

Trial lead investigator Professor Johann de Bono, head of the drug development unit at the ICR and The Royal Marsden said: “Our hypothesis is that advanced prostate cancers that progress on all available treatments remain dependent on androgen receptor signalling. HSP90 is necessary for the functional stabilisation and processing of the androgen receptor protein, and also supports several signalling pathways that control cell growth and resistance to apoptosis, while abiraterone targets an enzyme involved in androgen synthesis. Combining HSP90 and abiraterone should offer a multi-pronged attack against androgen receptor signalling and therefore cancer growth. We hope this strategy will lead to further treatment options for this clinically important disease.”

PI3 Kinase Inhibitor Zytiga Combo

Clinical trials are being carried out on the use of a PI3 kinase inhibitor in combination with Zytiga. PI3 kinase is involved in VEGFR stimulated angiogenesis and is involved in the growth of tumour metastases. PI3 kinase is also believed to mediate the resistance pathway and so a PI3 kinase inhibitor should help prevent Zytiga resistance. Salvestrols are natural inhibitors of the PI3 kinase pathway that have already been used in combination with Zytiga to combat resistance. The new drug PX-866 is a potent irreversible inhibitor of PI3 kinase and is currently undergoing Phase 2 clinical trials in comination with Zytiga and Prednisone.

Ongoing phase 2 trial of PX-866 in patients with recurrent or metastatic castration-resistant prostate cancer to include an additional group of up to 25 patients whose disease has begun to progress while receiving abiraterone (Zytiga) and prednisone.

PX-866 is a small molecule compound that is a Wortmanin analogue designed to inhibit the activity of phosphatidylinositol-3-kinase (PI3K), a component of an important cell survival signaling pathway.
PX-866 will be administered in addition to continuing treatment with Zytiga and prednisone. The primary endpoint of each part of this single-arm screening trial is the proportion of patients with lack of disease progression at 12 weeks from the initiation of therapy with PX-866.

PX-866 is an irreversible pan inhibitor of the PI3K/PTEN/AKT pathway, a critical cell signaling pathway that is activated in many types of human cancer. Aberrant activation and regulation of PI3K is implicated in a large proportion of human cancers, where it leads to increased proliferation and inhibition of apoptosis (programmed cell death). Natural inhibitors of PI3K such as salvestrols and wortmanin restimulate the cancer cells to undergo apoptosis.

FDA Issues Warning on Xtandi

The FDA have issued a warning on the Xtandi label concerning the risk of seizures. The seizure risk has recently increased from 0.6% to 0.9%. In the clinical trial of Xtandi in 800 men with prostate cancer there are now 7 reported seizures up from the earlier figure of 5 seizures.

Xtandi is a fat soluble molecule that has a half life of 7 days. This means that it will build up in fatty tissues upon repeated daily dosing and could reach critical levels in heart tissue, which would explain its cardiotoxicity.

WARNINGS AND PRECAUTIONS

Risk of Seizure

In the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures.

The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold.

Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

The most common adverse drug reactions (≥ 5%) reported in patients receiving XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients.

Xtandi - Xpensive - Xtortion !

Xtandi the new drug for the treatment of advanced prostate cancer has been launched at the extortionate price of $ 7,450 per month. This is exacting a high price from desperate people with prostate cance who may not be covered by medical insurance. How can anyone afford this treatment ? A lot of prostate cancer sufferers have keenly watched the progress of MDV3100 through clinical trials over a number of years each time waiting for the next results on this drug. Having finally gained FDA approval a lot of prostate cancer sufferers feel let down by the very high price for this medication. The price of Xtandi needs to be set lower than that of Zytiga in order to compete with it.

Xtandi Vs Zytiga

When it comes to comparing Xtandi with Zytiga there is no comparison - Zytiga wins handsdown on performance and price. Zytigas benefits go way beyond overall survival and there is an observable reduction in PSA levels together with a reduction in bone mets. Xtandi still has to stand the test of time in real clinical use and it will be interesting to see how it performs in this respect. Its hard to see how Xtandi will compete with Zytiga especially as it is priced considerably higher. Lets compare the 2 drugs:

Xtandi (Enzalutamide, MDV3100)
Price $7,500 per month
Oral Drug
Dose: 160 mg per day
Overall Survival Benefit: 4.8 months
Drawbacks: Cardiotoxic seizure risk
Advantage: No prednisone required

Zytiga (Abiraterone Acetate, CB7630)
Price $5,000 per month
Oral Drug
Dose: 1000 mg per day
Overall Survival Benefit: 4.6 months
Drawbacks: Prednisone coadministered
Advantage: Good safety profile and proven clinical benefits

The price of Xtandi at $ 7,500 per month is prohibitively expensive for all but the richest men with prostate cancer. The annual cost is $ 89,000 so this is aimed at the Provenge end of the market which costs $ 93,000 per treatment. However Provenge is FDA approved pre chemotherapy while Xtandi is FDA approved post chemotherapy so Xtandi would have to be paid for privately and used off-label to compete with Provenge. Who can afford to pay $ 7,500 per month privately? Not many I would think.

Will the clinicians deem the extra cost of Xtandi worthwile when compared to Zytiga ? Unlikely since this is still an experimental treatment and they may want to see more evidence for its safety.

Xtandi is a Cyano Benzene

Xtandi contains a cyano benzene group in its molecular structure. Xtandi is the trade name for Enzalutamide (MDV3100) a chemical whose real name is 4-[3-[4-Cyano-3-(trifluoromethyl)phenyl]- 5,5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl]-2-fluoro-N-methylbenzamide. So the real chemical name reveals this is a cyanide containing molecule. It also contains a thiohydantoin group which is found in insecticides which may explain its cardiotoxic side effects.

The chemical structure of Xtandi shows the cyanide group (NC-) attached to a benzene ring revealing it to be a cyano benzene derivative. This class of compounds are known to have toxic side effects and are used in weedkillers.

The drug also undergoes CYP2C8 mediated N-demethylation in the liver liberating formaldehyde which is hepatotoxic.

Xtandi is Just Another Flutamide Analogue

Xtandi the newly approved prostate cancer treatment is just another version of the existing agents Flutamide and Casodex (Bicalutamide). Xtandi is referred to as a "Super Casodex" and this is a fitting description, but this can also be looked at as "Expensive Casodex".

Flutamide usage in prostate cancer therapy goes back over 30 years and today costs $62 per month. Flutamide is activated in the liver to the metabolite hydroxy flutamide.

Casodex (Bicalutamide) is a more recent development and mimics the active hydroxyflutamide metabolite and this drug costs £432 per month.

Xtandi (Enzalutamide) has just received FDA approval and comes on the market at an astonishing $7500 per month.

So Xtandi is just an expensive version of Casodex and so far there are no clinical results to suggest that Xtandi is any better than Casodex in clinical practise.

Xtandi Cardiotoxicity Explained by Vioxx Similarity

Xtandi (Enzalutamide) has been FDA approved but comes with a seizure risk warning on the label. Xtandi has a biarylcyclopentane molecular structure that is very similar to the drug Vioxx which was withdrawn from the market due to cardiotoxic risks. The APPROVE study showed an increased risk of cardiotoxicity with Vioxx compared to a placebo and a similar trial should be conducted on Enzalutamide.

Molecular Structure of Enzalutamide (Xtandi)

Molecular Structure of Rofecoxib (Vioxx)

Rofecoxib is an anti inflammatory agent that works as a selective COX-2 inhibitor. Rofecoxib was approved by the FDA on May 20, 1999, and was marketed under the brand name Vioxx.
Rofecoxib gained widespread acceptance among physicians treating patients with arthritis and other conditions causing chronic or acute pain. Worldwide, over 80 million people were prescribed rofecoxib at some time.
In 2004 Merck withdrew rofecoxib from the market because of concerns about increased risk of heart attack and stroke associated with long-term use. Merck withdrew the drug after disclosures that it withheld information about rofecoxib's risks from doctors and patients for over five years, resulting in between 88,000 and 140,000 cases of serious heart disease. Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market. In the year before withdrawal, Merck had sales revenue of US$2.5 billion from Vioxx. By the time it was discontinued in 2004, it had already caused an estimated 60,000 deaths worldwide.

Was FDA Approval of Enzalutamide Too Fast

Enzalutamide has been approved by the FDA in an unprecedented time of only 3 months and shows how fast the FDA can work when pressurised to do so. But where is the pressure on the FDA to approve Enza;utamide coming from ? Why have the FDA approved Enzalutamide so quickly ? And who gets to profit from this decision ? The normal priority review time is 6 months and can take up to 12 months to review some drugs. Have the side effects of Enzalutamide been thoroughly investigated - unlikely in a 3 month review. The cardiotoxic side effects of Enzalutamide should be more thoroughly investigated before licensing this drug.

Enzalutamide - Have You Seen the Price ?

Now that Enzalutamide has been FDA approved for prostate cancer treatment post chemotherapy it will be launched as a competitor to Zytiga - But have you seen the price ? $7,500 dollars per month ! How can that compete with Zytiga at $ 5,000 per month. Surely the manufacturers of Enzalutamide now marketed as "Xtandi" need to set a price lower than Zytiga in order to compete, and to come up with a better name !. With the dose of Enzalutamide being only 160 mg per day then they could undercut Zytiga which is used at 1000 mg per day. The cost per kilo of enzalutamide works out at $ 1,562,000 per kg, whereas Zytiga is $ 167,000 per kg and so Enzalutamide is considerably more expensive than Zytiga. It will be interesting to see how well Xtandi competes with Zytiga in clinical use.

Xtandi - What Sort of a Name is That ?

First it was MDV-3100, then it morphed into Enzalutamide only to finally emerge as "Xtandi" What ? Who ? Where is Xtandi coming from, it sounds like a second hand mobile phone but I guess the marketing guys at Medivation know what they are doing. The FDA approval of Xtandi for prostate cancer patients that have received docetaxel chemotherapy launches Xtandi as a rival to Zytiga so it will be interesting to see how they compete head to head in the post chemotherapy setting. Xtandi Vs Zytiga game on !