Problems with Alpharadin ASCO SRE data?

At the 2012 American Society of Clinical Oncology (ASCO) annual meeting, data was presented by Dr Oliver Sartor (ASCO 2012 Abstract 4551) that showed radium-223 (Alpharadin) significantly delayed time to first skeletal-related event (SRE) in patients with castratation-resistant prostate cancer (CRPC) and bone metastases.

The SRE data for radium-223 from the ALSYMPCA phase III trial was first presented at ASCO GU earlier this year.

ASCO 2012 radium-223 data discrepancies

Algeta in a communication I received today, however, have advised that the data contained in the ASCO 2012 abstracts has “discrepancies.” In the absence of more precise information, the discrepancies may or may not be significant.

As with good practice, the sponsors have conducted further verification of the ALSYMPCA SRE data in preparation for the US FDA NDA regulatory submission. This has resulted in changes in the numbers previously reported for SRE data in the ASCO 2012 abstracts (Abstract #4551, LBA #4512). Though discrepancies were noted, the overall interpretation of the results has not changed. The SRE data will be disclosed once all additional data verification and analyses activities are completed.

Mike Booth, Algeta Communications & Corporate Affairs, June 15, 2012 email communication.

While the message that radium-223 significantly delays time to first SRE may not have changed, data accuracy is important and should not be taken lightly.

In his ASCO 2012 prostate cancer poster discussion, Evan Yu, Associate Professor at the University of Washington, made no mention of any “discrepancy.” Instead he used the data in Sartor’s poster that showed the time to first SRE with radium-223 to be 13.6 months versus 8.4 months with placebo, a delay of 5.1 months.

Dr Parker presented updated ALSYMPCA trial data at ASCO 2012 that showed a 5.5 month delay in time to first SRE with radium-223 (12.2 versus 6.7 months). Dr Sartor’s poster was based on 541 patients on radium-223, while Dr Parker’s data was for 614 patients. This suggests that the two presentations represent data at different time points.

Were Bayer and Algeta aware of the issues at the time of ASCO and chose not to say anything? Obviously, if the discrepancies are small or insignificant then it would not make much difference, but a large difference would be more of a concern.

What is the accurate SRE data for radium-223 from the ALSYMPCA trial?

I look forward to a future press release from Algeta/Bayer clarifying this, and hope that they will advise ASCO if corrections need to be made to the data previously presented and published.

Update on Orteronel TAK-700 from EAU 2012 Paris #EAU12

There are no major presentations of phase III clinical trial data at the European Association of Urology (EAU) Congress in Paris this weekend, but interesting clinical and scientific data is still being presented.

If you want to understand the competitive dynamics of the prostate cancer market and the market opportunity with urologists, then you need to be at meetings such as EAU in Europe and AUA in the United States.

There was a lot of interest in yesterday’s advanced prostate cancer poster session at EAU 2012.

I mentioned in a previous post that the radium-223/Alpharadin poster showed the data on skeletal-related events presented last month at ASCO GU in San Francisco.

Another poster that caught my attention for a variety of reasons was the one on orteronel (TAK-700), something that we have not heard too much about.

Activity and Safety of the Investigational Agent Orteronel in Men With Nonmetastatic Castration-resistant Prostate Cancer and Rising Prostate-specific Antigen: Results of a Phase 2 Study

Orteronel (TAK-700) is a selective, non-steroidal inhibitor of 17, 20 lyase, a key enzyme involved in the production of androgens such as testosterone. This is a similar mode of action to abiraterone acetate (Zytiga) that was approved last year in the US & Europe.

Orteronel is being developed by Millennium. Two phase III castration-resistant prostate cancer trials are currently enrolling. The post-chemotherapy trial (NCT01193257) is scheduled to have a primary completion date of September 2013 and the chemotherapy-naïve trial has a primary completion date of January 2013 (NCT01193244) according to clinicaltrials.gov at the time of writing.

It is worth noting that both phase III trials are using the drug in combination with prednisone. I doubt very much that the chemotherapy-naïve trial will show overall survival results by January 2013 (a date earlier than the post-chemo trial). This date must reflect when data on the primary outcome measure of radiographic progression free survival (rPFS) will be obtained.

Does rPFS correlate with overall survival? Many oncology new products have shown progression free survival, but no overall survival.

Is there a market for a “me too” of abiraterone? By the time orteronel comes to market, MDV3100 and Alpharadin will both most likely be approved, plus we will have greater insight into combinations and sequencing by then.

In talking to urologists, there is a clear preference for drugs such as MDV3100, which do not require the administration of concomitant steroids.

The phase II data in the poster presented at EAU yesterday concluded:

In patients with nmCRPC and rising PSA, single agent oral orteronel, at a dose of 300 mg BID without prednisone, was feasible and had manageable toxicities.

While it may be possible to administer orteronel without steroids, given the mechanism of action would it still be as effective? The authors also noted in the poster that 2 patients (out of 38) discontinued treatment due to adrenal insufficiency, suggesting that giving the drug without steroids is going to require active surveillance.

Finally, in thinking about TAK-700, I’m left with the question of whether phase III placebo controlled clinical trials are still ethical in advanced prostate cancer patients? In the post-docetaxel indication, we now have cabazitaxel and abiraterone approved, both of which offer an overall survival benefit. MDV3100 and Alpharadin are also expected to be approved by the FDA later this year.

If we have four new agents available after docetaxel that offer a survival advantage, is it ethical for men with advanced prostate cancer to be offered a placebo? If not, then this means that new products will have to go head-to-head with one of the approved drugs, or offer some additive effect if used in combination.

It will be interesting to see if this important issue is taken up by any of the patient advocacy groups and whether physicians start to raise concerns. Recruitment into placebo controlled trials could end up slower as a result.

Orteronel to me is too similar to abiraterone, which I think will face serious challenge from MDV3100. What the market opportunity for Millennium will be as a result of being late to market is an open question.

ASCO GU: radium-233 Alpharadin significantly prolongs time to first Skeletal Related Event

The abstracts for the forthcoming American Society of Clinical Oncology 2012 Genitourinary Cancers Symposium (ASCO GU) have been released and offer insight into some of the new data that will be presented at the meeting.

The results of the phase III ALSYMPCA trial for radium-223 (Alpharadin) in prostate cancer were presented at ECCO/ESMO last September by Dr Chris Parker.

As expected, there is no change to data presented in Stockholm that showed radium-223 (Alpharadin) improves both Overall Survival and Skeletal Related Events:

radium-223 Overall Survival Benefit
median 14.0 vs 11.2 months; P value = 0.00185; HR = 0.695

radium-223 time to first SRE
median 13.6 vs 8.4 months; P value = 0.00046; HR = 0.610

However, the meeting abstract published today shows that radium-223 in bone-metastatic castration resistant prostate cancer patients (CRPC), not only significantly prolonged time to first skeletal related event (SRE), but significantly prolonged 3 out of the 4 SRE components:

time to spinal cord compression,
time to pathological bone fracture
time to external beam radiation

No significant improvement in the SRE component of time to surgical intervention was seen with radium-223.

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Preview of ASCO GU 2012 Prostate Cancer Data

After the recent JP Morgan Healthcare conference, San Francisco remains the destination of choice for forthcoming medical meetings.

Yesterday, saw the start of the 2012 ASCO Gastrointestinal Cancers Symposium (ASCO GI) at Moscone West from Jan 19-21.

In a few weeks time, the 2012 ASCO Genitourinary Cancers Symposium (ASCO GU) will be held at the San Franciso Marriott Marquis from Feb 2-4.

If you are based in San Francisco, you are at the heart of the action. It’s less optimal if you are East Coast based, unless you need the frequent flyer miles and have a good travel budget!

According to the ASCO GU preliminary program there are eight oral abstracts on prostate cancer that will be presented at the meeting on Thursday, February 2. Here’s my preview of a few that caught my attention:

ASCO GU Abstract #1:

MDV3100 Phase 3 AFFIRM trial results

The first presentation of the MDV3100 AFFIRM phase 3 trial results are a late-breaking abstract and my prediction for the highlight of the prostate cancer session at ASCO GU.

So far, all that is known from the November 3, 2011 press release from Medivation/Astellas is that MDV3100 produced a 4.8 month advantage in median overall survival compared to placebo in men with advanced prostate cancer.

This met the primary endpoint of the phase 3 AFFIRM trial, and the study was stopped early as a result. As the press release notes, MDV3100 provided a 37% reduction in risk of death compared to placebo (hazard ratio = 0.631).

Howard Scher (MSKCC) will present the AFFIRM trial results at ASCO GU, and a closer look at the MDV3100 data is eagerly awaited.

ASCO GU Abstract #6:

Effect of denosumab on prolonging bone-metastasis-free survival (BMFS) in men with nonmetastatic castrate-resistant prostate cancer (CRPC) presenting with aggressive PSA kinetics.

Amgen are seeking a new indication for denosumab (Xgeva) in prostate cancer on the grounds that it prolongs bone metastasis-free survival in men with non-metastatic CRPC. The supplemental Biologics Application (sBLA) for denosumab will be discussed at the Oncologic Drugs Advisory Committee (ODAC) meeting on February 8, 2012.

The results from the phase 3, 147 trial were published in The Lancet last November and showed that use of denosumab delayed time to first bone metastasis by 3.7 months and improved bone-metastasis free survival.

Sally Church on Pharma Strategy Blog wrote about the denosumab 147 data presented at the annual meeting of the American Urological Association (AUA 2011) last year.

However, the challenge that Amgen faces is that they have yet to show that use of denosumab in men with prostate cancer results in an improvement in overall survival. While it may delay the spread of prostate cancer to the bone, the gold standard for all the prostate cancer drugs approved to date has been overall survival.

The 147 trial showed that overall survival was similar between those taking placebo and those receiving denosumab (HR 1.01; 95 percent CI: 0.85, 1.20; p=0.91). Hypernatremia and osteonecrosis of the jaw were also reported with a higher frequency in the denosumab group

It is possible that there may be updated data at ASCO GU, but most likely it will be a review of The Lancet data with some subset analysis.

The FDA Center for Drug Evaluation & Research (CDER) plans to provide a free of charge, live webcast of the February 8, 2012 meeting of the Oncologic Drugs Advisory Committee, so I am looking forward to what the committee makes of Amgen’s filing.

ASCO GU Abstract #7:

Vitamin E & the Risk of Prostate Cancer – updated results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT)

Eric Klein will be presenting updated results from the SELECT trial that were previously reported in the October 12, 2011 issue of the Journal of the American Medical Association (JAMA).

The data showed a 17% increase in prostate cancer risk with Vitamin E supplements. Although the program abstract advertises updated data, I’m not expecting the data to differ dramatically from last year’s JAMA paper.

ASCO GU Abstract #8:

Overall survival benefit and safety profile of radium-223 chloride (Alpharadin), a first-in-class alpha-pharmaceutical: Results from a phase III randomized trial (ALSYMPCA) in patients with castration-resistant prostate cancer (CRPC) with bone metastases.

The ALSYMPCA trial data is being presented for the benefit of attendees who did not hear Oliver Sartor’s presentation on radium-223 (Alpharadin) at the NY Chemotherapy Foundation or hear Chris Parker present the trial data at ECCO/ESMO in Stockholm. This makes strong commercial sense, especially as it’s a product that physicians in the United States may know little about.

I blogged extensively about the ALSYMPCA trial results presented last year, and had the privilege to do an interview with Chris Parker from the Royal Marsden Hospital at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO/ESTRO) in Stockholm.

I am not expecting new data to be presented at ASCO GU on radium-223, but it will be interesting to see how the audience views a bone targeted radio-pharmaceutical that unlike denosumab, does provide an overall survival benefit.

The ALSYMPCA trial showed a significant delay in time to first skeletal-related event (SRE) of 13.6 months vs 8.4 months:

AND a median overall survival of 14 months compared to 11.2 months for placebo group:

Alpharadin is on the fast track to FDA approval this year.

My conclusion: If you plan to be at ASCO GU 2012, the prostate cancer data to watch is the first presentation of the MDV3100 AFFIRM trial results.

Prostate Cancer Session at AACR-NCI-EORTC Molecular Targets San Francisco

By Pieter Droppert on November 17, 2011

The recent AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics international conference in San Francisco was an informative meeting.

What I particularly liked was the strategic overview that took place in many of the plenary sessions.

As an example, Johann de Bono, Professor of Experimental Cancer Medicine at The Institute of Cancer Research/The Royal Marsden in London highlighted the potential drug development targets based on prostate cancer biology:

Androgen Receptor (AR)
Heat Shock Proteins (Hsp)
Signaling: HER3, MET, IGF-1R, CCL2, IL-6, Src
PI3K/AKT/TOR signaling
PARP and BRCAness
Estrogen receptor (ER)
c-MYC & CHK1

His presentation discussed the possible therapeutic approaches, and complexity involved in developing novel targeted therapies for prostate cancer.

This is something that I expect we will hear more of at the AACR special conference on Advances in Prostate Cancer Research early next year.

In particular, de Bono discussed drug development strategies to target androgen receptor signaling, and some of the future challenges including:

Proving to the regulatory authorities that circulating tumor cell (CTC) count falls are a robust immediate endpoint of overall survival
Developing improved imaging for bone metastases

As a side note, there were several posters for cabozantinib (XL184) at the meeting (available on the Exelixis website), including preliminary research on computer-aided quantitative bone scan assessment.

However, as de Bono mentioned in his presentation, “diffusion weighted MRI shows hot spots not detected by bone scans.”

2010 and 2011 were good years for prostate cancer drugs, and with new approvals for MDV3100 and radium-223 (Alpharadin) expected, 2012 is set to be another “grand cru” year, to paraphase Bertrand Tombal.

If you were not able to make it to San Francisco for the Molecular Targets and Cancer Therapeutics conference, webcasts of many sessions will be available on the AACR site.

Chemotherapy Foundation Symposium Prostate Cancer Update

This morning the 8am session at the Chemotherapy Foundation Symposium (The Greenspan Meeting) in NYC featured a review of current developments in Prostate Cancer.

The informative 1.5 hour session covered a lot of ground with the presenters reviewing clinical data for:

Radium-223 Chloride: a new option for CRPC (Oliver Sartor)
Pomegranite extract for Rising PSA (Michael Carducci)
XL184 in mCRPC (David Smith)
Optimizing patient selection for sipuleucel-T (Simon Hall)
Intermittent androgen suppression for prostate cancer (Laurence Klotz)
Lenolidomide/docetaxel in CRPC (Daniel Petrylak)

The highlight, in my opinion, was Oliver Sartor’s excellent presentation on radium-223 chloride (Alpharadin) in which he cogently outlined its mechanism of action. He explained that radium-223:

targets osteoblastic bone metastases by acting as a calcium mimic
is a bone-seeking calcium mimetic that binds to hydroxyapatite
has preferential uptake in areas of new bone formation

As mentioned previously on this blog, there are critical differences between an alpha emitter such as radium-223 and other bone-seeking radiopharmaceuticals that are beta emitters.

Sartor presented some excellent slides that showed how alpha emitters require much fewer DNA hits to kill cells, are short range and have a higher initial energy per particle. In other words they are very effective at short range within the bone microenvironment, something that Chris Parker from The Royal Marsden Hospital mentioned in his interview from ECCO/ESMO in Stockholm.

Sartor concluded his Chemotherapy Foundation Symposium presentation by reflecting on “where do we go from here” in prostate cancer? Some of his observations were:

We are currently in a sequencing paradigm. Drug A then B then C
We need to combine active agents to give the best results, that is our next challenge
How are we going to afford it all?

Sartor succinctly highlighted where the rubber currently hits the road, and left the audience with plenty to reflect upon. I am sure we can expect further debate on sequencing and combination possibilities at medical and scientific meetings in 2012.

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MDV3100 shows survival in Advanced Prostate Cancer

Prostate cancer is the second leading cause of cancer death in men, so it was good news this morning when Medivation & Astellas issued a press release that showed positive data from the phase 3 AFFIRM trial for MDV3100.

MDV3100 produced a 4.8-month advantage in median overall survival compared to placebo.

The estimated median survival for men treated with MDV3100 was 18.4 months compared with 13.6 months for men treated with placebo.

MDV3100 provided a 37 percent reduction in risk of death compared to placebo (Hazard Ratio=0.631).

To put the 4.8 month survival advantage in context, this compares favorably with 3.9 months for abiraterone (Hazard Ratio =0.646), in the COU-AA-301 trial.

Positive data was expected given the sound scientific rationale behind MDV3100 and the preliminary data (abstract 4501) presented at the ASCO annual meeting this year. J Clin Oncol 29: 2011 (suppl; abstr 4501).

The drug has a high affinity for the androgen receptor (AR) that is highly expressed on prostate cancer cells. You can read an excellent interview on Pharma Strategy Blog with Charles Sawyers, who was one of the co-inventors.

MDV3011 blocks the androgen receptor (AR) from moving into the nucleus and activating growth genes and is a more complete inhibitor of AR than bicalutamide.

One hot topic of conversation at ASCO was the potential to combine MDV3100 (androgen receptor blocker) with abiraterone acetate (Zytiga) (androgen synthesis inhibitor), thereby shutting down upstream and downstream activity of the driving receptor in advanced prostate cancer. The scientific rationale for this appears sound, so it is likely that a combination clinical trial may well be done to test this hypothesis at some point in the future.

MDV3100 has a significant advantage over abiraterone acetate (Zytiga) in that concomitant steroids are not required. Daily steroids have their side effects. Urologists in particular will be attracted to MDV3100 and its ease of use.

Clinical trials in prostate cancer are ongoing with a multitude of new emerging therapies including TAK-700, Cabozantinib (XL184), radium-223 chloride (Alpharadin), BPX-101, Prostvac-VF, ipilumumab, Custirsen (OGX-011), dasatinib (Sprycel), lenalidomide (Revlimid) and ARN-509 to name but a few.

It is a therapeutic area with a lot going on after very little activity for a decade. The positive interim data for MDV3100 announced today is good news for prostate cancer patients, and we await presentation of the data next year.

Medivation and Astellas plan to hold a pre-NDA meeting with the U.S. Food and Drug Administration (FDA) in early 2012, so US approval could be possible later next year.

Insights from Society for Translational Oncology Prostate Cancer Symposium

By Pieter Droppert on October 31, 2011

The Oncologist Journal of the Society for Translational Oncology (STO) has published a video recording on prostate cancer that is well worth watching for those with an interest in this area.

At their Sept 8, 2011 CME symposium held in Belfast, a roundtable was held entitled “Prostate Cancer: Progress & Promise.”

Moderated by Bruce A. Chabner (Mass General/Harvard), the panelists were Joe O’Sullivan (Queen’s University, Belfast), Johann De Bono (The Institute for Cancer Research) and David Waugh (Queen’s University, Belfast).

Professor de Bono in the video comments that”

“with regards to our dream of eventually treating men with prostate cancer without castrating them, which must be our ultimate goal and curing them of cancer. I think we will have to focus on for example drugs targeting ERG or ERG signaling.”

Chabner then asks the good question of whether ERG is a druggable target?

To which De Bono replies that you can drug ERG by inhibiting PARP and references a paper by the Chinnaiyan group published in the May 2011 issue of Cancer Cell.

PARP inhibition represents an interesting area of prostate cancer research.

If you would like to know more, Sally Church, PhD has written about this on Pharma Strategy Blog. See posts on “TMPRSS2: ERG may be a more useful marker than PSA in prostate cancer” and “Personalized Therapy for Prostate Cancer – is it possible?”

In the STO video, De Bono discusses why he would like to replace bone scans in prostate cancer with another imaging modality that more accurately reflects the activity of the disease. Future possibilities include use of diffusion weighted magnetic resonance imaging and novel PET tracers.

There’s also a good discussion about Alpharadin for those interested in some anecdotal commentary on experiences with it.

Another notable comment by De Bono is his belief that “taxanes work in prostate cancer primarily by targeting androgen receptor signaling.” Taxanes have typically been thought to target mitosis.

De Bono goes on to say that clinical trial data being submitted for publication shows that patients who are refractory to abiraterone, are also refractory to docetaxel when they progress on it. The suggestion is that there may be cross resistance between abiraterone and taxanes with a subgroup of patients who just don’t do well on androgen receptor (AR) targeting drugs. The reason for this isn’t yet clear.

A new phase 2 clinical trial is starting soon that will look at the sequencing of abiraterone and cabazitaxel. One group will receive abiraterone followed by cabazitaxel, the other cabazitaxel followed by abiraterone.

The Belfast STO symposium was the second in a three part series. The next one will be held during ASCO GU in San Francisco next year.

Another potentially useful meeting in this area is the February 2012 AACR workshop on “Advances in Prostate Cancer Research” chaired by Arul Chinnaiyan & Charles Sawyers.

Prostate cancer remains an exciting therapeutic area to watch with tremendous progress and promise of late.

A year in review on Biotech Strategy Blog

By Pieter Droppert on October 26, 2011

Biotech Strategy Blog is 1 today! I can’t believe that a year has gone by so quickly! Before moving on to year 2, I thought a brief review might be interesting.

What have been the top posts on Biotech Strategy Blog this past year?

In terms of total visitors per post:

For those who like metrics:

Highest number of reads per month was in May (19,927)
Year to date there have been 79,179 visitors
Most visited day was September 22, 2011 (2136 reads)

What have been some of the other posts that I enjoyed writing about?

My top 5 (not in rank order) would be:

Finally, I have produced 4 videos that you can watch on the biotechstrategy channel on YouTube.

http://youtu.be/nDvY7opm3Fs

http://youtu.be/_oAJ1fU0PT4

http://youtu.be/hM_wmjaqDyc

http://youtu.be/i5GNBmuISqQ
It’s been a busy but enjoyable year. Biotech Strategy Blog is still a work in progress. If you have enjoyed a particular series of posts or would like me explore a topic or theme in the future, do email me or post a comment.

radium-223 Alpharadin in Advanced Prostate Cancer – an interview with Dr Chris Parker

Radium-223 (Alpharadin) is a novel bone targeted treatment for advanced prostate cancer.

At the recent European Multidisciplinary Cancer Congress in Stockholm (EMCC 2011), Dr Chris Parker from The Royal Marsden Hospital presented results of the phase 3 ALSYMPCA trial that showed both delayed time to first skeletal-related event (SRE) AND an overall survival (OS) benefit for those men with advanced prostate cancer taking radium-223. This is the first time a product in the bone category has shown such a survival benefit – neither denosumab or zoledronic acid can claim that distinction.

Unlike the recent regulatory approvals for cabazitaxel (Jevtana) and abiraterone acetate (Zytiga), which focused on the post-docetaxel setting, the ALSYMPCA trial included not only those who had already received cytotoxic therapy, but also pre-docetaxel patients, who were unable to take chemotherapy.

As Dr Parker mentions in the interview that he kindly gave in Stockholm (the first video interview on Biotech Strategy Blog), radium-223, assuming it gains regulatory approval, will provide a new treatment option for the considerable population of men with bone metastases who may be too weak, too old or otherwise unable to take chemotherapy such as docetaxel.

Radium-223 is, therefore, potentially good news for this “neglected” population of prostate cancer patients.

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Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘Alpharadin’

Update on Orteronel TAK-700 from EAU 2012 Paris #EAU12

Activity and Safety of the Investigational Agent Orteronel in Men With Nonmetastatic Castration-resistant Prostate Cancer and Rising Prostate-specific Antigen: Results of a Phase 2 Study

Prostate Cancer Session at AACR-NCI-EORTC Molecular Targets San Francisco

Chemotherapy Foundation Symposium Prostate Cancer Update

MDV3100 shows survival in Advanced Prostate Cancer

Insights from Society for Translational Oncology Prostate Cancer Symposium

A year in review on Biotech Strategy Blog

radium-223 Alpharadin in Advanced Prostate Cancer – an interview with Dr Chris Parker

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