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Posts tagged ‘Xgeva’

Radium-223 (Alpharadin) will be “Practice Changing” is how Michael Baumann, President of the European CanCer Organisation (ECCO) and Jean-Charles Soria, Co-Scientific chair of the 2011 Stockholm Multidisciplinary Cancer Congress described the prostate cancer clinical trial data to be presented in the Presidential (plenary) session on Saturday September 24, 2011.

Alpharadin is the first bone targeted therapy to show an overall survival (OS) advantage in metastatic castration-resistant prostate cancer (mCRPC). To date, none of the other therapies targeting bone in prostate cancer such as zoledronic acid (Zometa), denosumab (Xgeva) or cabozantinib (XL184) have shown any overall survival benefit.

The Alphardin data from the phase 3 ALSYMPCA trial that will be presented in Stockholm shows an increase in overall survival of 2.8 months compared to placebo (median OS of 14 months with Alpharadin versus median OS of 11.2 months with placebo, p=0.00185, HR=0.695).

What is big news is that Alpharadin also significantly prolongs time to first skeletal related event (p=0.00046; HR=0.610). This is tremendous news for prostate cancer patients given the number that experience bone metastases.

It is not, however, good news for Amgen and denosumab (Xgeva). Amgen have tried to associate the improvement in symptoms and decline in skeletal related events with survival, but have failed to obtain any overall survival data (OS). This is something that Alphardin achieves as well as a significant reduction in time to first skeletal related event (SRE).

What Alpharadin has effectively shown is that by nuking bone metastases using a weak alpha emitting radium-223, overall survival (OS) can be prolonged in a way that targeting rank ligand does not. This is ground breaking news and the 2011 Stockholm Multidisciplinary Congress have rightly recognized the importance of this data with a plenary session. For further information on how Alpharadin works – see my previous blog post about the ASCO 2011 phase 2 data.

At the press briefing late friday afternoon in Stockholm, Dr Chris Parker of the Royal Marsden Hospital and PI of the ALSYMPCA study said that “Radium-223, a novel alpha-pharmaceutical, may provide a new standard of care for the treatment of  CRPC patients with bone metastases.”

There is no doubt in my mind that it will lead to a new standard of care. What’s more as Dr Parker speculated in the press briefing, there is no reason why Alphardin could not be combined with androgen receptor antagonists such as the recently approved abiraterone acetate (Zytiga).

Both are well tolerated and operate by different mechanisms of action.  It’s hard not to believe that the overall survival of CRPC patients will be increased by such a combination.

When approved, Alpharadin and any possible combination with Zytiga, may further delay the use of sanofi-aventis’ cabazitaxel (Jevtana) in the post-doctaxel CRPC setting. It may also potentially have an impact on the use of sipuleucel-T (Provenge) in the asymptomatic population.

The Alpharadin phase 3 trial results is exciting news from the 2011 Stockholm Multidisciplinary Cancer Congress. I will be writing more after Dr Parker presents the data in the Presidential session later today.

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Earlier this week Bayer & Algeta announced that Alpharadin™ (radium-223 chloride) had received Fast Track designation from the FDA for the treatment of castration-resistant prostate cancer (CRPC).

Bayer signed an agreement with Norwegian based Algeta in 2009 for the global commercial rights to Alpharadin™, with Algeta retaining a 50/50 co-promotion and profit-sharing in the United States.

According to the Algeta August 23, 2011 press release, in light of the FDA fast track designation they plan on filing for United States approval in mid-2012, ahead of previous expectations.

At the ASCO annual meeting in Chicago this year, phase II clinical trial data for Alpharadin™ was presented during the poster session (Abstract #4620).  You can obtain a copy of the poster here.

ASCO Alpharadin™ Phase 2 Data showed increase in Overall Survival

What impressed me when I saw the poster and talked to Gillies O’Brien-Tear, the Chief Medical Officer for Algeta, was the increase in overall survival (OS) seen. In the phase 2 study presented, Alpharadin™ improved OS by 4.5 months versus placebo when added to the standard of care in patients with CRPC and bone metastases.

To me this stands out from other drugs that are targeting bone metastases in CRPC, such as cabozantinib (XL184) and denosumab (Xgeva®), where to my knowledge no overall survival benefits have yet been seen.

Despite the lack of OS benefit, Amgen announced earlier this week on Aug 22nd, they had made a supplemental BLA application for denosumab to expand the indication to include the prevention of bone metastases in CRPC. The PDUFA date is April 12, 2012.

Will Xgeva® and Alpharadin™ be viewed as potential competitors or used synergistically? It will be interesting to see any data that shows the impact of Alpharadin™ on bone pain and quality of life, and how physicians view the new treatment options that may be available to them.

How does Radium-223 chloride act? 

It is a calcium mimetic that is taken up by bone, where the radium then emits alpha-particles that act on the prostate cancer bone metastases.  The radiation is only short range (2-10 cell diameters) which limits its toxicity to healthy tissue and results in localized and focused radiation that kills metastatic cancer cells in the bone.

The day after the phase 2 results were presented at ASCO, Algeta and Bayer announced on June 6, positive data from the interim analysis of the phase 3 ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer patients) trial.

This study began in June 2008, with enrollment of 922 patients completed in January 2011. According to the June 6 press release, the interim analysis of the ALSYMPCA trial showed a statistically significant increase in overall survival in CRPC patients receiving Alpharadin™ compared to placebo.

Median overall survival was 14.0 months for Alpharadin™ and 11.2 months for placebo (two-sided p-value = 0.0022, HR = 0.699)

As a result of the interim analysis, the independent data monitoring committee recommended that the trial be stopped and patients on the placebo arm offered treatment with Alpharadin™. Dr Chris Parker, from the Royal Marsden Hospital, and Principal Investigator of ALSYMPCA, said:  

“Based on the observed survival benefit and its safety profile, Alpharadin may become an important treatment for patients with bone metastases from advanced prostate cancer.”

At the forthcoming European Multidisciplinary Cancer Congress in Stockholm (co-sponsored by ECCO, ESMO and ESTRO), the phase III Alpharadin data for the ALSYMPCA trial will be presented as a late breaking abstract on September 24, 2011 in the Presidential Session.

The abstracts for the meeting are not yet available, but in the light of the FDA Fast Track designation earlier this week, and the fact the ALSYMPCA trial results will be presented in a plenary session at Stockholm, positive data is expected.

The prostate cancer market is certainly heating up with the approval earlier this year of Zytiga™ (abiraterone acetate) and several products in late stage development such as Alpharadin™, MDV3100, TAK-700 and custirsen (OGX-011). It’s good news for patients that new treatment options may be available before too long.  As to how these new therapies are used, sequenced and combined, that is set to be the topic of conversation at medical and scientific meetings over the coming year.

Launch of Zytiga (abiraterone acetate) at 2011 annual meeting of American Urological Association (AUA) in Washington DCThe market for prostate cancer therapies is set to expand from $1 billion currently to $5 billion by 2015, according to analysts reported by this morning’s Washington Post/Bloomberg news.  This is perhaps no surprise given the recent approval of abiraterone acetate (Zytiga®) from Ortho Biotech (JNJ).

New clinical data on prostate cancer clinical trial results is expected at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago this weekend from many of the prostate cancer therapies in development such as MDV3100, TAK700, ARN-509, cabozantinib (XL184), ipilimumab, custirsen (OGX-11), BPX-101, alpharadin, denosumab (Xgeva®) and Prostvac-VF.

Indeed, one could argue that prostate cancer is becoming a competitive marketplace.  Any emerging biotechnology company that is not already developing a prostate cancer drug is likely to find it a hard market in which to create a blockbuster.  By the time any drug comes to market, there will be incumbents with effective products who have captured market share.

Prostate cancer is an exciting market to watch from a marketing strategy and patient perspective, as several companies potentially bring new products to market over the next few years.

However, the bottom line is that patients will live longer as a result of all the innovation that is taking place.  Not only that but physician education and awareness of how to treat this disease is also likely to improve as they seek out knowledge on new therapies and treatments.  This to many will make a major difference.  At the recent American Urological Association (AUA) annual meeting, the sessions on treatment of prostate cancer were standing room only.  There is clearly a demand for knowledge out there as the treatment paradigms change.

At the other end of the spectrum, there is also innovation taking place in terms of improved diagnosis and treatment of prostate cancer.  Whether we should screen all men for PSA remains a controversial topic, although use of risk calculators do appear to offer less false positives.  Indeed, calculating risk is going to be one of the key areas that primary care physicians and urologists need to focus on, particularly in the light of the PIVOT trial data that was presented at AUA, showing radical prostatectomy (with risks including incontinence and erectile dysfunction) was not better than watchful waiting in low-risk, early stage disease.

However, a presentation I am looking forward to at ASCO 2011 is on circulating tumor cells (CTC) and whether these can be a prognostic or even a predictive biomarker.   Both the phase III MDV3100 and abiraterone acetate clinical trials captured CTC data.  It will be exciting news at ASCO 2011 if circulating tumor cells that require only a blood sample offer an improvement over PSA not only for detection of prostate cancer, but in monitoring the disease over time.

I will be at ASCO 2011 this weekend, and look forward to writing more on prostate cancer from the conference!

There is a lot of focus at the annual meeting of the American Urological Association (AUA) here in Washington DC on metastatic castrate resistant Prostate Cancer (mCRPC), and the recently FDA approved adrenal steroid inhibitor, abiraterone acetate (Zytiga®).

Drugs in development that target the androgen receptor, such as MDV3100, are also generating a lot of interest from urologists.

However, Oliver Sartor (Tulane) in the Saturday morning satellite symposia that I attended, focused on emerging therapies in CRPC, beyond the androgen axis. His hypothesis:

“Cancers are devious and some of the mechanisms of AR activation appear to be ligand-independent and resistant to all current androgen-axis targeted therapies.”

What this means is that focusing on adrenal steroid inhibition or blocking the androgen receptor may not be sufficient to prevent disease progression. If we are looking for a Prostate Cancer cure, then will it take multiple drugs, including those that target various stromal sites? That is the intriguing question that Sartor raised.

Indeed, if there is one take home from this meeting, it is that the “desert” of prostate cancer therapies has now blossomed into a multiplicity of potential new therapies and development, which will mean that urologists and oncologists will soon be spoilt for choice as abiraterone and MDV3100 are not the end of the story.

Sartor highlighted some interesting ones on the horizon to watch out for:

Alpharadin: This is a bone targeted therapy that uses radioactive Radium 223 to kill cancer cells. It is being developed by Norwegian company, Algeta in partnership with Bayer Schering Pharma AG. The 900 patient phase III trial completed accrual earlier this year in Jan 2011. Phase II data was published in the Lancet in 2007 by Nilsson et al. Data from alpharadin will be “coming soon” according to Sartor.

XL-184 (cabozantinib): Activated MET is highly expressed in prostate bone metastases. Exelixis XL-184 is a small molecule tyrosine kinase inhibitor that specifically inhibits both MET and VEGFR2.

Data from a phase 2 study of XL-184 in castrate resistance patients was presented last year at the EORTC-AACR-NCI Symposium on Molecular Targets and Cancer Therapeutics in Berlin by David Smith et al (Abstract 406).

Both XL-184 and alpharadin would be potential competitors to Amgen’s denosumab (Xgeva®).

Other new products in development “Beyond the Androgen Axis” that Dr. Sartor mentioned included Prostvac-VF, BPX-101 and ipilimumab. A phase III trial of ipilimumab, both pre- and post- docetaxel is now underway in mCRPC. A phase III trial of Prostvac-VF will start later this year with 1200 patients in a placebo controlled study with minimally symptomatic, castration-resistant metastatic prostate cancer patients.

Over the next few years a lot of data may emerge on exciting new treatment options. Coupled with the basic research that is going on, tremendous progress in the treatment of Prostate Cancer is already taking place.

According to Sartor “multiple drugs will be necessary to cure mCRPC and that is our greatest challenge today.” Major progress is now being made towards this.

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I am off to Washington DC tomorrow for the annual meeting of the American Urological Association (AUA).

If you are not able to attend, then you can follow the Twitter coverage on Pharma Strategy Blog where Sally Church (@MaverickNY) will be aggregating the tweets.  The conference hashtag is #AUA2011.  I also expect to be live-tweeting from the conference.

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Like many medical conferences in the United States, the AUA meeting kicks off with independent continuing medical education (CME) satellite symposia on topics of interest.

As a lawyer who has to pay for his own continuing legal education (CLE) credits, I have to confess that I am somewhat cynical that other professionals such as physicians expect to have their CME paid for through free industry-sponsored events.  These symposia are certainly not cheap to run.

However, compared with Europe, CME events in the United States are usually well-produced and fair balanced, albeit with a topical theme that obviously relates to the sponsor’s interest.

The two satellite symposia that I will be attending at AUA are Friday evening’s Amgen supported “Managing Skeletal-Related Events in Patients with Prostate Cancer” and the Saturday morning Astellas/Medivation supported “Reason for Hope: Key Advances in the Management of Castration-Resistant Prostate Cancer.”

While at Quintiles, I was lead CRA/European Project Manager for the phase III trial trial of risedronate in elderly women at risk of hip fracture, so I am interested in bone related treatments, and am looking forward to hearing more about denosumab (Xgeva®) and its impact on skeletal related events (SRE).

Oliver Sartor (Tulane) raises some excellent questions in a recent paper published in the Asian Journal of Andrology, “if a patient has a SRE, does it affect the way a patient feels, functions or survives?”

Sartor argues that a better definition of the benefit a drug has on SRE’s would be “a reduction in pain, analgesic consumption or improvement in quality of life (QoL)” instead of the current “feel, function or survive” standard.

He notes that patients with bone-metastatic castrate resistant prostate cancer (CRPC) have a limited life expectancy, so that QoL is a key issue. “An asymptomatic event linked to a future adverse event is less meaningful in a patient with metastatic CRPC.

Sartor concluded his paper by saying:

“The lack of effect of bisphosphonates or denosumab on patient-reported outcomes including QoL, pain or analgesic consumption continues to be a disappointment for this entire field.”

When we talk about a reduction in SRE’s what does this really mean for the patient?  I look forward to hearing what the expert panel at Friday evening’s symposia on this topic and hope it will be addressed.

Moving on to the other satellite symposium, supported by Medivation/Astellas, that I will be attending early on Saturday morning.  I expect this symposium will focus on new drugs in the pipeline such as MDV3011 and ARN-509 that target the androgen receptor. Hopefully they will also discuss other therapeutics, such as the recently approved abiraterone acetate (Zytiga®), as well TAK-700, which has a similar mechanism of action to abiraterone, i.e. they both inhibit CYP17 and testosterone production.

I’m looking forward to hearing what the expert panel has to say about the need to take prednisone with abiraterone, and whether there are any issues surrounding long-term usage if abiraterone ends up being used earlier in the pre-chemotherapy setting.  Updated data from the COU-AA-301 trial will be presented at AUA on Monday, and I expect a lot of interest from urologists in this.

The satellite symposia are set to be a good warm up act to the start of the main AUA meeting that runs from May 14 to 19 in Washington DC.  I’ll be writing more from the AUA 2011 over the next few days.

ResearchBlogging.orgSartor, O. (2011). Denosumab in bone-metastatic prostate cancer: known effects on skeletal-related events but unknown effects on quality of life Asian Journal of Andrology DOI: 10.1038/aja.2011.33

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