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Details Matter When Interpreting Xtandi Data

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Medivation stock went down after the results of the trial. Why?

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Before the bell on January 22, Medivation (MDVN) reported data from a large randomized Phase II trial of its prostate cancer drug Xtandi (aka enzalutamide). The data were from the 'TERRAIN' trial. TERRAIN tested Xtandi in earlier-stage prostate cancer - one step earlier than is on the current FDA label for Xtandi.

The TERRAIN trial was successful, showing a high degree of efficacy for Xtandi versus Casodex, an existing generic drug many urologists use after men see their PSA rise while on Lupron. If you look at Medivation's stock chart, however, you'll see the company's stock topped out at $111.20 the day before the positive TERRAIN data were released.

TERRAIN was strongly positive, which usually means a rise in the stock price. Yet Medivation's shares have lagged (a little) since the release. So where's the disconnect with Medivation and the TERRAIN trial?

Before I dig into the data, it must be acknowledged there are many specialists and generalists in the biotech space who are in profit-taking mode. This could merely be a sell-the-news event. After all, it is less than two weeks since the release of the top-line TERRAIN data and Medivation hasn't even had a chance to present the full data at a scientific conference.

I don't think this is just 'sell the news', however, which is why I'm penning this article.

The TERRAIN data were spectacular. The primary endpoint of progression-free survival (PFS) was hit with a Hazard Ratio (HR) of HR=0.44 at a p-value of p < 0.0001. Translated (roughly translated), this means any patient has a 56% chance of doing better (more days without his disease progressing) on Xtandi than if he took Casodex (56% comes from the inverse of the 0.44 hazard ratio). Further, the outcome is highly statistically significant.

The median patient in the TERRAIN trial had a PFS of 15.7 months on Xtandi versus 5.8 months on Casodex. So the median patient avoided his disease progressing for ~10 months longer by taking Xtandi than if he took Casodex. The median patient in TERRAIN stayed on Xtandi for 11.7 months.

Great data. So why'd the stock go down?

Remember the TERRAIN trial is for a patient population a step earlier in prostate cancer than the current Xtandi label. Xtandi received approval last year for treating metastatic patients before they receive chemotherapy based upon the PREVAIL trial. PREVAIL was also a huge success and is one reason why Xtandi is displacing Johnson & Johnson's (JNJ) competitive drug Zytiga in the pre-chemo setting. In the PREVAIL trial, the median patient was on Xtandi for 16.6 months.

And this "time on drug" is where people are getting hung up... In PREVAIL, patients were on Xtandi for 16.6 months. In TERRAIN, they were on Xtandi for 11.7 months. Looking at these two data points, people were wondering why Xtandi was "less effective" in TERRAIN than PREVAIL. There were even doctors in my Twitter feed who said they wouldn't use Xtandi in the earlier-stage TERRAIN patients because the drug 'worked better' in later stage patients. And it is admittedly unusual a cancer drug would be "worse" in earlier stage disease. So, some people were worried.

Not so fast...

A quick glance at TERRAIN and PREVAIL would lead the casual observer to believe they both share the same PFS endpoint (which directly influences time on drug). The biotech investor who digs into the data knows better.

TERRAIN's definition of progression was any of the following:
• Radiographic progression in tissues, or
• Skeletal event (any bone scan lesion or bone injury/break), or
• Initiation of a new cancer drug

PREVAIL's definition of progression was any of the following:
• Radiographic progression in tissues, or
• Two new bone scan lesions

You can clearly see TERRAIN and PREVAIL have quite different "PFS" endpoints. Specifically, TERRAIN's "initiation of a new cancer drug" component is important.

TERRAIN patients have earlier stage disease without metastatic disease. The easiest way to tell if these patients are progressing is their PSA value. If the PSA goes up, the treating doctor assumes the disease is progressing and will switch the patient to a different therapy even if he doesn't show any metastatic disease on his scans. With PSA in the mix in TERRAIN, where it wasn't in the mix in PREVAIL, the reason for a shorter time on drug in TERRAIN is clear.

(Real prostate cancer geeks will recognize the difference bone scan criteria also contribute, but that's a way too long/geeky a topic for this article.)

When the full TERRAIN data are presented later this year (probably mid-May, but perhaps earlier), everyone will get a better idea of this point. But biotech investors who watch the data know a comparison of time on drug between TERRAIN and PREVAIL is largely meaningless given how the PFS endpoints are completely different.

(It's also worth pointing out the control arm in TERRAIN is an FDA-approved, active drug (Casodex) while the control arm in PREVAIL is placebo. This also makes comparisons between PREVAIL and TERRAIN difficult.)

Medivation has a companion trial to TERRAIN called 'STRIVE' that should report data later in Q1 or perhaps in Q2. STRIVE is in a slightly different patient population, but I expect Xtandi will be better than Casodex in STRIVE as well. Wall Street will want to compare PREVAIL and TERRAIN and STRIVE, but smart biotech investors will need to remember there are subtle but important differences making comparisons difficult.


Twitter: @AlpineBV_Miller

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