Pivotal Discontinuation Ends Tokai Misery Early

| About: Tokai Pharmaceuticals (TKAI)

The business case for Tokai Pharmaceuticals’ (NASDAQ:TKAI) lead prostate cancer project, galeterone, was questionable well before today’s 70% collapse in the group’s share price.

And the problems were more fundamental even than the fact that the castrate-resistant prostate cancer field has been shaken up beyond recognition by Johnson & Johnson’s (NYSE:JNJ) Zytiga and Medivation’s (NASDAQ:MDVN) Xtandi. By halting galeterone’s phase III study for futility today the trial’s data-monitoring committee has put Tokai out of its misery early.

Indeed, realization that galeterone’s proposition did not hold water had slowly been dawning on investors for some time: between Tokai’s $112m, September 2014 Nasdaq float and yesterday its stock had fallen 72%. This morning Tokai opened down another 70%, with a market cap of just $34m – below its $44m first-quarter cash balance.

Head to head...

At issue was the group’s pivotal Armor3-SV trial in a planned 148 prostate cancer patients carrying the AR-V7 splice variant mutation, in which galeterone was being compared head to head against Xtandi.

This morning Tokai said that, based on the data-monitoring committee’s decision that Armor3-SV would likely fail to show galeterone’s superiority in terms of radiographic progression-free survival, the study was being discontinued. It said this unplanned review had occurred after the committee saw unblinded data during a routine meeting.

The halt raises serious doubts about the already thin case for galeterone and its purported triple mechanism of action. This, Tokai had claimed, involved Zytiga’s CYP17 lyase inhibition and Xtandi’s androgen receptor antagonism, as well as promoting androgen receptor degradation.

It is undeniable that AR-V7 mutations, whereby Zytiga or Xtandi-treated patients relapse because of the formation of a truncated isoform of the androgen receptor, are a huge unmet need. Dramatic survival differences have been shown between AR-V7-negative and positive patients (Asco-GU preview: First-line prostate cancer chemo not dead yet, February 24, 2015).

However, relapsed patients were not the ones Armor3-SV was targeting, based on the earlier observation in a small study that it was treatment-naive patients who responded to galeterone. This is why Tokai designed Armor3-SV as a complex trial in which it would first screen at least 1,500 untreated patients for presence of the AR-V7 splice variant to identify the 148 who would be enrolled.

...fails all the same

The big surprise is that galeterone failed even in this setting – which in the real world would have required a medical practice change as well as a companion diagnostic.

This is especially curious since, if AR-V7-positive patients had been selected and the AR-V7 hypothesis held true, Xtandi should have shown zero activity. The best explanation Tokai could offer was that its understanding of AR-V7 was still evolving.

For now the group is continuing enrolment into a separate phase II trial, Armor2, testing galeterone in 144 prostate cancer patients who have acquired resistance to Xtandi. But if galeterone does not work in Xtandi-naive patients it is hard to see mechanistically how it might work in those with acquired resistance.

Since galeterone has failed even in the narrow treatment-naive setting the project is probably a write-off. Xtandi and Zytiga resistance continues to be a key drug development opportunity, but it seems that little short of a mechanism directly targeting the AR-V7 splice variant will cut the mustard.

Selected Tokai studies of galeterone

Study

Design

Status

Trial ID

Armor3-SV

148 treatment-naive AR-V7 pts, vs Xtandi

Phase III (discontinued)

NCT02438007

Armor2

144 Xtandi-resistant pts

Phase II

NCT01709734

Xtandi or Zytiga-resistant pts

Planned

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