Takeda’s orteronel (formerly known as TAK-700) may be on its way to “dog drug heaven” after an interim analysis of the ECM-PC 5 phase 3 clinical trial showed that men with advanced prostate cancer taking the drug did not live significantly longer (HR 0.894, p=0.226) than those taking an inactive placebo. Here’s a link to the Takeda press release.
Johnson & Johnson (JNJ) just announced the acquisition of privately-held Aragon Pharmaceuticals and the rights to ARN-509 a second-generation androgen receptor antagonist that will be a future competitor to Medivation’s Xtandi.
The deal, valued at $1billion, with $650M upfront and $350M based on contingent milestone payments, is a blow to Medivation who have been locked in litigation with Aragon and the University of California over ownership of the rights to ARN-509. Both ARN-509 and Xtandi were developed in the laboratories of Charles Sawyers and Michael Jung at UCLA.
The Aragon acquisition is a sound strategic decision for JNJ, offering them the ability to develop their prostate cancer franchise after Zytiga goes off patent and more importantly, offer a product that at the very least is equivalent to Xtandi, and potentially, may be superior. ARN-509 will also allow JNJ to compete in earlier stages of prostate cancer with a drug that does not require use of steroids, something that has always been a major problem for Zytiga in the chemotherapy-naïve setting.
JNJ now have a corporate strategy for life post-Zytiga. They have the resources and expertise to fund large phase III clinical trials for ARN-509, not only in prostate cancer, but potentially also in breast cancer. Aragon being bought out by a big Pharma with deep pockets is a blow to Medivation/Astellas.
What this acquisition also tells us is that Johnson and Johnson lawyers consider the Medivation appeal over intellectual property rights to be weak. They will no doubt have done considerable due diligence on Medivation’s claims and consider the risk to be low or manageable.
My personal view was that cash-rich Medivation should have acquired Aragon themselves and neutralized the competitive threat rather than pursue a scorched-earth litigation strategy.
The JNJ acquisition of Aragon also suggests that ARN-509 may be perceived as the best in class of the second-generation androgen receptor inhibitors in development. There are others that JNJ could have sought to acquire or licence, including ODM-201 (Orion). The fact that JNJ chose ARN-509 or a better version of Xtandi is not good news for other companies with AR antagonists in early-stage development.
Medivation are unlikely to feel the competitive threat from ARN-509 in the prostate cancer market for a few years, because registration trials against the current standard of care are needed to show that the drug offers an equivalent or better survival benefit. ARN-509 will most likely be compared against Zytiga, offering yet another benefit of the deal – the ability to provide free comparator drug in the clinical trials.
The JNJ acquisition is good news for men with advanced prostate cancer who may in 5 years see another new treatment option become available. It is, however, a blow to Medivation and Astellas who now have a serious competitor to deal with in the future in a space where they may have thought they had a major competitive advantage.
Men 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.