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.
Thursday, 20 September 2012
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.
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.
Tuesday, 18 September 2012
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.
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.”
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.”
Saturday, 8 September 2012
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.
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.
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.
Friday, 7 September 2012
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.
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