It's been a while since I took a look at what's happening in the prostate cancer arena, but it seems a good time after the recent flurry on lung and colorectal cancers, especially as it's Groundhog Day :-).
There are three particular agents that I'm interested in:
I'm going to spend most of this post talking about the first two, as much has been said on Dendreon already.
Dendreon filed their amended BLA on November, and the FDA have given a PDUFA date of 1 May 2010. The data from 512 patients showed an improvement of 4 months survival for Provenge over placebo, meeting the FDA's threshold.
We have, however, no idea how the vaccine would have done compared to standard chemotherapy such as docetaxel plus prednisone, and therein lies the rub. Normally, in oncology trials we compare the standard of care with and without the new agent or compare the standard therapy to a different regimen. Placebo controlled trials have not done well with ODAC and the FDA, as J&J, Vion and Genzyme all learned with placebo controlled trials in elderly AML patients.
Regular readers of Pharma Strategy Blog will know I'm not a big fan of either placebo trials in cancer or vaccines, so we'll wait and see what the FDA decide. My expectation is that it will receive approval this time round having jumped through the extra hoops.
Cougar Biotech and J&J are developing abiraterone in advanced prostate cancer. A phase III trial in asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer began enrolling this month.
It's estimated to complete in April 2014 and the primary endpoint is overall survival, but initial results should be available in April 2011 for progression free survival at 12 months from what I can see, so perhaps there will be some data around ASCO in 2011. Based on that data I can't see a filing much before the 2nd half of 2011 at the very earliest, possibly not until 2014.
Looking at J&J's analyst presentations, I found the following timeline for their pipeline:
Now, many drugs are lumped together in the 2011 timeframe across 3 columns. It isn't clear whether each column represents 2011, 2012 and 2013 or it's a random list of drugs that will be filed in that period. Either way, it's hard to see abiraterone getting accelerated approval so my assumption for now is abiraterone will be filed in 2013, with approval in 2014.
It's not going to be a fast development: Cougar is very inexperienced and J&J are relatively weak and slow in oncology.
The asymptomatic nature of the patients will also complicate things because it's a high risk study that may not show much in the end. If it works, great! That said, I'm not sure how well the results will fare in what looks like a fluffy trial design comparing abiraterone plus prednisone to placebo plus prednisone. Patients are specifically excluded if they have received prior chemotherapy. Well then, why not compare abiraterone to docetaxel, which is the current standard of care in castration-resistant disease, given that this is a front-line trial?
Recently, at the AACR Molecular Targets meeting in Boston, I had the pleasure of listening to a most excellent talk from Dr Charles Sawyers (MSKCC), one of may favourite researchers. He covered a lot of ground on the lessons learned in targeted agents, principally in CML and prostate cancer.
With regards to prostate cancer, he showed a graphic similar to this one (from Medivation):
Clearly, there are a number of opportunities to explore for the development of new drugs for the disease after hormome therapy ceases to work. This is where traditional drug development for chemotherapies typically starts.
What was interesting about Sawyers talk is his discussion about the androgen receptor (AR) and whether or not it is important in castration resistant disease.
Previously, AR was thought to be irrelevant in this situation because it is not expressed in 2 common prostate cancer cell lines, but Sawyers argued cogently that this shows a failure to appreciate the potency of inhibition because AR is restored through PSA production. Several reasons have been evaluated for this, including AR amplification, mutation and alternative pathways among others. AR is also overexpressed in castration resistant xenograph models, and can confer castration resistance.
What followed was an elegant discourse showing that MDV3100 is distinct from bicalutamide, whereby it has a greater affinity, binds AR selectively, without displaying agonism in AR overexpressing cells and has more potent antagonistic activity.
In the end, Sawyers argued that what was important was not AR overexpression per se, but AR amplification because prostate cancer cells with natural AR amplification are more sensitive to AR knockdown than AR single copy prostate cancer. Minor AR knockdown is sufficient to inhibit growth of AR amplified disease. All of this leads us logically to an important question:
Are AR amplified prostate cancers a different (and important) patient subtype?
Clinical trials with MDV3100 have demonstrated that at least half of prostate cancer patients remain AR dependent, suggesting that this is indeed the case. Clearly, if you can keep patients hormone sensitive or at least responding to therapies using different approaches, then the opportunity to delay time to metastasis and late stage disease may well exist with these novel approaches.
Time will tell.