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

Posts tagged ‘ASCO 2012’

At the 2012 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Oliver Sartor, Professor of Cancer Research and Medical Director of the Tulane Cancer Center in New Orleans told attendees in the educational session on castration-resistant prostate cancer (CRPC) that he was tired of being asked the question of what is the optimal sequence for new advanced prostate cancer drugs?

ASCO 2012 CRPC Prostate Cancer Education SessionThere is “No data,” Sartor told the ASCO 2012 audience. As a result he recommended the use of less toxic therapies first and that patients be involved in the decision making. Not quite the guidance the audience perhaps hoped for.

Sartor is, however, correct that we don’t yet have the data – the clinical trials have yet to be done that will answer the question of what is the optimal sequencing of prostate cancer drugs?

The approval of abiraterone acetate (Zytiga®) for the treatment of men with advanced prostate cancer, post chemotherapy, and the expected approval of enzalutamide (formerly MDV3100) and radium-223 (Alpharadin) have focused attention on sequencing and combination options.

A poster at ASCO 2012 showed that cross resistance may occur between abiraterone and enzalutamide, suggesting that if resistance to one develops it may lower the efficacy to the other if given subsequently. More data and research is needed to validate this finding and understand how resistance develops.

Reciprocal feedback between the PI3-Kinase and androgen receptor (AR) signaling pathways means that blocking the androgen receptor may stimulate the PI3K pathway and vice versa, leading to the tumor trying to ensure its survival. This is particularly important in prostate cancers that have the PTEN tumor suppressor gene, the result is that the targeting of both PI3K and the AR to avoid crosstalk may be required.

The scientific rationale for combining enzalutamide with a PI3-kinase inhibitor was discussed on Pharma Strategy Blog in Sally Church’s video from the 2011 American Urological Association annual meeting. Clinical trials are being planned to investigate the use of PI3-kinase inhibitors in prostate cancer.

I have written more from ASCO 2012 about the emerging challenges in prostate cancer drug development in a guest post published on Xconomy.  Many thanks to Luke Timmerman, National Biotech Editor, for the opportunity to contribute.

Hopefully, there will be more insights available at ESMO 2012 later this year and at ASCO next year on prostate cancer drug resistance, optimal sequencing and the benefits that combinations therapies may offer.

Abiraterone Acetate Pre-Chemotherapy ASCO 2012Men with advanced prostate cancer want to know “if I take this drug, will I live longer?” Unfortunately, for abiraterone acetate (Zytiga®) in the pre-chemotherapy setting i.e for asymptomatic or mildly symptomatic men, doctors will only be able to say, “maybe” and tell the patient there is a strong trend towards an overall survival (OS) advantage.

You can read my Xconomy article published yesterday, on why I think it was a mistake for the abiraterone acetate COU-AA-302 trial (302 trial) in chemotherapy-naïve (pre-chemo) men to be stopped early.  The results were presented on Saturday at the American Society of Clinical Oncology (ASCO) meeting in Chicago.

Understanding the Lan-DeMets alpha spending function with O’Brien-Fleming boundary based on number of death events observed is challenging for non-experts.

However, the bottom line is that the 302 trial failed to meet the pre-specified hazard ratio for stopping early, and by so doing it failed to meet one of its co-primary endpoints. This is disappointing because the trial most likely only needed another 92 deaths to occur before it would have reached significance, and this would have occurred in a matter of months.

The co-primary endpoint of radiographic progression free survival (rPFS) was, however, met in the 302 trial. Whether rPFS reflects tangible clinical benefit is unknown.  The FDA have (to my knowledge) not approved a prostate cancer drug on the basis of rPFS , overall survival remains the regulatory standard.

I also learnt for the first time at ASCO about the problem of bone flare in patients receiving abiraterone. Charles Ryan, MD who presented the 302 data, discussed this is an ASCO educational session on prostate cancer imaging.

Bone scan flare is a spurious, “worsening” bone scan in the context of clinical response that reflects increased intensity of lesions, not new lesions.  In other words a brighter image on a bone scan may not represent disease progression.

In a previously published study, Dr Ryan showed a 43% incidence (10/23) of bone flare with abiraterone.  He advised attendees at the ASCO 2012 educational session to “look for, and CONFIRM new lesions before calling progression based solely on bone scans.”

Although the rPFS data for the COU-AA-302 trial was read centrally, and is therefore presumed to be more reliable as a result, I would have welcomed more discussion on the extent rPFS correlates with survival following the COU-AA-302 data presentation at ASCO.  I expect the Oncologic Drugs Advisory Committee (ODAC) will vigorously discuss this in more detail when Johnson & Johnson seek a pre-chemotherapy indication for abiraterone based on the COU-AA-302 data.

Bearing in mind overall survival has been the de facto standard in advanced prostate cancer, it will be interesting to see how the FDA and ODAC will view what is essentially a failed trial with a non-significant OS.  Will precedent be broken, opening the floodgates for future sponsor submissions based on PFS?

Update January 24 2013: FDA & EMA approve Zytiga Pre-Chemo in CRPC

With little fanfare and no ODAC, the FDA issued a press release on December 10, 2012 announcing that abiraterone acetate (Zytiga) had received approval “to treat men with late-stage (metastatic) castration-resistant prostate cancer prior to receiving chemotherapy.”

The press release states: “The FDA reviewed Zytiga’s application for this new indication under the agency’s priority review program. The program provides for an expedited six-month review for drugs that may offer major advances in treatment or provide a treatment when no adequate therapy exists.

The fact that there was an unmet need for prostate cancer treatments prior to chemotherapy was clearly key to their decision making. The press release notes that “patients who received Zytiga had a median overall survival of 35.3 months compared with 30.1 months for those receiving the placebo.”

However, the FDA in their carefully worded press release make no mention of the fact that the difference of 5.2 months in median overall survival failed to reach the pre-specified value for statistical significance.

In other words, although JNJ have expanded the label for abiraterone to include the pre-chemo indication, they cannot make the claim that taking abiraterone prior to chemotherapy definitely results in men living longer (overall survival). All we can say is that the data was trending towards a statistically significant overall survival advantage. To many this may seem academic, but overall survival remains the benchmark that drives cancer drug development and by which treatment effectiveness is judged.

As I noted in my post from ASCO 2012 for Xconomy, most likely statistical significance for overall survival would have been reached in a few months, which is why I and others thought the trial had been stopped too early. I would be surprised if other companies follow JNJ’s strategy, and expect Medivation will seek to show a significant overall survival advantage for enzalatumide (Xtandi) in their pre-chemotherapy PREVAIL trial.

Johnson & Johnson announced on January 11, 2013 that abiraterone has also received approval in the European Union for the pre-chemotherapy prostate cancer indication following a positive recommendation from the Committee for Medical Products for Human Use (CHMP) of the European Medicines Agency (EMA).

It will be interesting to see if there is any new data in the updated interim analysis for the COU-AA-302 trial (abiraterone pre-chemo) that will be presented at the 2013 ASCO Genitourinary Cancers (ASCO GU) symposium in Orlando next month.


ASCO 2012 ChicagoThis morning I am heading off to the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago from June 1 to 5, 2012.

Finalizing my conference schedule yesterday afternoon led me to reflect that at major meetings with multiple parallel sessions, one of the keys to success is having a plan before you arrive. 

This year, ASCO have the best Congress eplanner that I have yet to see, and what’s more you can not only create and print an online schedule or export it as an Excel spreadsheet, but sync it with your iPad or iPhone/Android conference app.

Congratulations to ASCO in creating an innovative app that cuts down on paper and makes it easier for attendees to plan their program!  For those attending ASCO for the first time, a few suggestions:

Tip 1:  Have a plan in advance of arriving

Whether this is to follow a cancer tumor type, or area of clinical development you want to learn about, have a draft plan of what you want to see and perhaps more importantly, which leading experts you want to hear.

Tip 2:  Be flexible & follow #ASCO12 live tweets

I am a great believer in the “law of two feet” which says if there’s something more interesting going on elsewhere & the session you are in is not delivering what you want, get up and leave.  Many times I have seen live tweets from a session that I was not in that turned out to be the place to be – Twitter can help you find the hot topics.

Tip 3:  Don’t be afraid to talk to people

Take time to network & meet people. Sounds obvious, but a lot of the science & data can be revisited on the outstanding virtual meeting program. This meeting is about making connections, whether you are a clinician, researcher, media or in the industry. I always try and talk to people on the ASCO bus from the hotel to the conference center – it’s fascinating to have a brief chat with people from all around the world who have a common aim to treat and cure cancer.

Thanks to @ldtimmerman I’ll be contributing some ASCO commentary to Xconomy next week and am excited about the opportunity. I’ll post the links when they are up.

If you are interesting in following the news from ASCO 2012 remotely, then Sally Church (@MaverickNY) will be aggregating live #ASCO12 tweets on Pharma Strategy Blog.

ASCO 2011 #BlisterWalkIt’s almost time to pack the comfortable shoes for the #blisterwalk (thank you @MaverickNY for that pithy description) across the bridge at ASCO 2012 in Chicago.

No matter what your ASCO program choices, attendees are destined like a modern day Sisyphus to walk the bridge repeatedly as your schedule takes you from one end of McCormick Place to the other.

I am looking forward to the new data expected at the meeting. For diehards who are at ASCO till the last day, next Tuesday will see Dr Chris Parker present updated data on the ALSYMPCA trial for radium-223 (Alpharadin) in advanced prostate cancer. We can expect to see an increase in overall survival (OS) from the 2.8 months presented in Stockholm last year. HT @BiotechStockRsr.

An increase in OS is not uncommon with time, the COU-AA-301 trial results for abiraterone acetate (Zytiga) increased from 3.9 months when initially presented, to 4.6 months at ASCO 2011 last year.

And for those for whom the official ASCO 2012 program is not enough, there’s a series of ancillary events most evenings ranging from an unofficial tweet up to investor presentations, faculty parties and CME events.

The unofficial tweetup hosted by @adamfeurstein and others will be at the Hubbard Inn this Friday from 6pm to 8pm. Last year it featured an eclectic mix of MDs, analysts, investors, Pharma/Biotech peeps, cancer advocates, science bloggers, journalists and PR mavens.  Welcome to the world of twitter – @3NT will see you there!

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