Pharma Strategy Blog

The interview with Dr Charles Sawyers from Memorial-Sloan Kettering recently, talking about his role in Medivation’s MDV3100, turned out to be rather good timing.  On Friday, Medivation announced their 1Q earnings and clinical progress.

The big news is that aside from the ongoing phase III trials in castrate-resistant prostrate cancer (CRPC) before (PREVAIL) and after failure of docetaxel (AFFIRM), the company are seeking to explore the use of MDV3100 earlier in the disease.  This makes a lot of sense, both clinically and strategically.  A phase II trial is already open in the pre-chemotherapy setting, comparing MDV3100 to bicalutamide (TERRAIN).

Highlights

1. The first phase II trial evaluates the combination of MDV3100 with bicalutamide in the treatment of advanced prostate cancer patients who have progressed while on LHRH analogue therapy or following surgical castration. TERRAIN is expected to enroll approximately 370 patients in North America and Europe. The primary endpoint of the trial is progression-free survival.  This trial is ongoing and patients are enrolling.
2. A second phase II trial has now opened and is the first trial to examine the effects of MDV3100 without medical or surgical castration.  Patients will be given MD3100 monotherapy and “enrolled patients would not have had any previous hormonal therapies for the treatment of prostate cancer.” In other words, both hormone and chemotherapy naive, so very early in the prostate cancer treatment cycle where LHRH analogues are traditionally given.  On Friday, Medivation announced that the first patient has now begun treatment with MDV3100 in this setting.  Approx. 60 patients will be enrolled in Europe, with PSA as the primary endpoint and will take MDV3100 orally for 24 weeks (160 mg dose).
3. The main phase III registration trial,  AFFIRM, is a randomized, double-blind, placebo-controlled study in 1,199 patients with advanced prostate cancer who were previously treated with docetaxel-based chemotherapy.   MDV3100 was compared to MDV3100 versus placebo.  The primary endpoint is overall survival.  The study completed enrollment last November, so Medivation plan an interim analysis  by the end of the year.

Interestingly, MDV3100 is now being positioned as “a triple-acting oral androgen receptor antagonist.” As Dr Sawyers noted in the interview, MDV3100 and abiraterone (Zytiga) have very different mechanisms of action in throttling either the androgren receptor signaling directly, or by inhibiting testosterone production that drives tumour growth through CYP17 inhibition.

What does all this data mean?

On Friday this week, I’ll be heading off to the annual meeting of the American Urology Association (AUA) and will be live tweeting, blogging and vlogging the event to see what urologists and oncologists think of these new developments.

Essentially, abiraterone’s recent FDA approval means that they will compete head to head with Sanofi’s cabazitaxel (Jevtana) in the post Taxotere setting, and Medivation look to be about 18 months behind with MDV3100, although the latter are aggressively expanding their trial program earlier in the disease, where I think it will have a more lasting impact.  The proof of concept for androgen receptor antagonists has already been proven with bicalutamide, so the question there is whether MDV3100 will be a more complete and effective inhibitor.  In the long run, a phase II trial combining abiraterone and MDV3100 to take advantage of their different mechanisms of action in early prostate cancer makes a lot of sense.

The last few weeks have provided some amusement with naysayers insisting that the PDUFA date for abiraterone wasn’t until October instead of realising it was getting Priority approval early (oops) and that the MDV3100 phase III trial couldn’t possibly be mature for an interim analysis by year end (another oops).  I’m glad I called both of those correctly 🙂

This leads me to ponder the next controversy – will urologists use these new hormonal agents in the pre-chemo setting once approved in the post chemo setting?  My hunch is yes based on the overwhelming feedback I heard this year at both ASCO GU and the European Association of Urology meeting in Vienna.

I say this with hindsight, knowing that many people insisted when imatinib (Gleevec) was approved for CML in refractory and advanced disease, that it wouldn’t be used front-line without FDA approval.  When we looked at the data at the end of 7 seven months from approval, guess what?  There was a fair bit of front-line use even without compendia listing, so it can happen when there is pent up demand and high desire to use a product.

My sense is that will happen here too, especially as bicalutamide and ketoconazole are already well established in the prostate cancer treatment paradigm as patients cycle through multiple therapies, but we will see.  Urologists, we all know, much prefer pills over the complexity of infusional therapies.

What’s next?

In the meantime, with another round of urology and cancer conferences coming up, we can expect to see the final OS survival data from the FDA submission for abiraterone presented at AUA by Fred Saad and an update on the much awaited circulating tumour cells (CTC’s) data from Prof De Bono at ASCO.  All in all, it’s going to be a very interesting two months!