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Posts tagged ‘Stockholm Cancer Congress 2011’

One piece of hot news at the 2011 European Multidisciplinary Cancer Congress (twitter #EMCC2011) taking place in Stockholm this weekend is the data on radium-223 chloride (Alpharadin) in metastatic castration resistant prostate cancer. The phase 3 ALSYMPCA trial results were presented in yesterday’s presidential symposia by Dr Chris Parker, Consultant Clinical Oncologist at The Royal Marsden Hospital.

Dr-Chris-Parker-Alpharadin-Presentation-Stockholm-Cancer-Congress-2011

The Scandinavian location for the presentation could not have been better, given that Alpharadin was developed by the Norwegian company Algeta. Bayer Schering Pharma AG have the worldwide commercial rights, but Algeta maintains a co-promotion option in the United States.

I first picked up on Alpharadin in a presentation given at the American Urological Association (AUA) annual meeting by Oliver Sartor (Tulane) earlier this year when he reviewed new prostate cancer products in development.

Algeta-Radium-223-Chloride-ASCO 2011-Abstract-4620At the ASCO 2011 meeting in Chicago there was a poster on the Alpharadin Phase 2 trial data (see the figure on the right) that caught my attention given that it showed an overall survival (OS) advantage.  This news was, however, largely drowned by the interest in cabozantinib (XL184).

The result is that Alpharadin has to many come out of left field. It is a promising compound for the treatment of prostate cancer that will provide new treatment options for patients with metastatic disease. In particular, use in combination with other therapies such as abiraterone acetate (Zytiga) may prolong survival to a greater extent than either does individually.

Currently, radium-223 chloride (Alpharadin) is only in investigational use and is not approved in Europe or the United States. It is, however, on the fast track towards FDA approval in 2012.

ALSYMPCA phase 3 prostate cancer data presentation ESMO ECCO 2011What makes Alpharadin exciting as a new treatment option for castration resistant prostate cancer (CRPC) is that the ALSYMPCA trial data shows that it not only provides a significant median overall survival (OS) benefit of 2.8 months compared to placebo (14 months versus 11.2 months, p=0.00185, HR 0.695), but significantly delays the time to first skeletal event by 5.2 months (13.6 months versus 8.4 months, p=0.00046, HR 0.610).

The overal survival (OS) benefit seen in the ALYSMPCA phase 3 trial is comparable to other approved agents in the post-docetaxel setting for CRPC. However, where it is unique is in the additional effect it has on skeletal related events (SRE), a common occurrence in metastatic prostate cancer.  Bone metastases are painful and have a significant impact on quality of life.

Other compounds that target the bone microenviroment such as denosumab (Xgeva), provide a delay in the time to first skeletal event in prostate cancer patients but to-date have not been shown to confer an overall survival advantage. This means that Alphardin is the first bone targeted agent to confer both an overall survival and a delay in time to first skeletal event.

After Dr Parker’s presentation of the ALSYMPCA phase 3 trial data yesterday here in Stockholm,  Professor Wim Oyen of the Department of Nuclear Medicine in Nijmegen discussed the data.

What he noted was the high tolerability of Ra-223 chloride (Alpharadin) as compared to other radiopharmaceuticals for treatment of patients with bone metastases.  He discussed how the emission of alpha particles allows for a short range effect (a few cell diameters) that is very localized, but with a large biological effect.

Oyen highlighted the “opportunity for improving patient outcome by adding Ra-223 in regimens of combination therapy,” something that Dr Parker speculated about in his media briefing.

Professor Oyen also saw “an opportunity for improving patient outcome by using Ra-223 in an adjuvant setting.”  His conclusion based on the phase 3 ALSYMPCA trial data presented was that radium-223 chloride (Alpharadin) is an “effective, very well tolerated and convenient treatment modality.

Algeta-radium-223-chloride-alpharadin

Dr Parker mentioned to me, while waiting for a train back to Stockholm, that the ALSYMPCA trial data he presented had not yet been submitted for publication. He said he would be disappointed if it did not appear in the New England Journal of Medicine. Given that it is groundbreaking and “practice changing,” I would be surprised if it is not published in the NEJM in due course.

I am sure that we will be hearing more about radium-223 chloride (Alpharadin) in the forthcoming months, especially now it is on fast track to FDA approval in 2012.

Although not a cure for prostate cancer, the ALSYMPCA trial data presented here in Stockholm is further good news for patients, and will provide a potential new treatment option for urologists and oncologists.

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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.

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