There are no major presentations of phase III clinical trial data at the European Association of Urology (EAU)
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.
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.
The 102nd Annual meeting of the American Association for Cancer Research (AACR) ended yesterday in Orlando, and it was only the diehards who kept going till the last session of the last day for an update on “Novel Androgen Receptor Antagonists.”
As I mentioned in an earlier post, there is a lot of excitement in the prostate cancer field at the moment with three new therapies approved last year (cabazitaxel, sipuleucel-T, denosumab), and more expected over the next two years (abiraterone acetate, MDV3100, cabozantinib/XL-184).
What I took from the AACR session I attended, is that there are also other products in the pipeline that are worth watching. Below is a list of some of the products that were mentioned. It’s not intended to be a comprehensive review of the prostate cancer landscape, only my notes and thoughts on some of the new products that the speakers touched upon.
Abiraterone Acetate: The postive phase III trial results were reported last year at ESMO and ASCO GU, and the approval of this drug is currently being considered by the FDA. Approval is expected shortly, and possibly in time for launch at the forthcoming annual meeting of the American Urological Association (AUA) meeting in Washington, DC.
Abiraterone (brand name Zytiga) inhibits the enzymes (17-alpha hydroxylase and C17, 20 lyase) responsible for adrenal androgen formation.
The phase III results were impressive in very sick patients who were close to the end of their lives in very advanced disease. Overall survival increased from 10.9 to 14.8 months in the second line chemotherapy setting post docetaxel. It’s expected that the results will be more dramatic pre-chemotherapy.
Once the FDA approval is obtained, it’s hard to see how oncologists will not consider abiraterone instead of cabazitaxel in the second-line chemotherapy setting. An easily taken pill with fewer less side effects may be a more convenient option for elderly or frail men with prostate cancer. Abiraterone’s approval will not be good news for sanofi-aventis.
I also expect we will see significantly off-label usage of abiraterone pre-chemotherapy by urologists as they seek to maintain hormone-sensitivity in their patients after several lines of anti-hormonal therapies. There is a phase III trial ongoing in this setting that is expected to show promising data by the end of the year.
However, it’s a good strategy to come market as soon as possible to provide wider access to patients in need, and the post-docetaxel second line setting allowed the overall survival benefit to be shown before the pre-chemo data would be available.
However, what I learned at the meeting is that abiraterone acetate may not be the best product in the long term. Currently it requires the corticosteroid, prednisone, to be given at the same time to attenuate the mineralocorticoid effects. Questions that were raised in the AACR session about long-term treatment with abiraterone included, “Must a corticosteroid be given concurrently?” and “What about hypertension?”
Other questions remain, such as possible development of resistance to abiraterone. Often the first drug to market is not the best, and it’s possible that second generation new products in the pipeline may be better than abiraterone and delay the time to resistance further.
However, what abiraterone does have is first mover advantage and depending on the pricing strategy adopted by Johnson & Johnson, the ability to capture market share earlier. It will be interesting to see what happens with this drug, but it’s certainly an exciting time for patients with prostate cancer.
TAK-700: This drug from Takeda/Millennium is a more potent inhibitor of C17α-hydroxylase than abiraterone. One of the panelists at AACR believed that TAK-700 “may in the long run surplant abiraterone acetate due to less need for mineralocorticoids.” TAK 700 entered phase III clinical trials late last year.
MDV3100: This drug is being developed by Medivation/Astellas and is also in phase III trials, with data expected by the end of this year or early 2012. It has a high affinity for the androgen receptor. However, what came across in the AACR presentation by Howard Scher, was his view that the second compound developed by Charles Sawyers, ARN-509 may be better than MDV3100.
ARN-509: This drug from Aragon Pharmaceuticals is in phase I/II clinical trials and is definitely one to watch. As Dr Scher pointed out, ARN-509 is more potent than MDV3100 and I expect we will see publication of more data on ARN-509 in the near future.
If you are interested in prostate cancer, AACR are offering webcasts and podcasts of scientific sessions this year. Further information can be found on their website. AACR have also announced a scientific special session on “Advances in Prostate Cancer Research” from February 6-9 2012. It’s certainly an interesting and exciting time in this field as new products become available, something that is likely to make a real difference to how this disease is treated.