Yervoy’s prostate cancer flop points the way to another combo

Bristol-Myers Squibb’s melanoma drug Yervoy is being studied in no fewer than 11 prostate cancer trials – a fact that might come as a bigger surprise than its phase III failure in this setting, announced yesterday.

The group clearly sees huge potential in prostate cancer, but the phase III readout shows that standalone Yervoy is probably a non-starter in this cancer type. Given the drug’s toxicity the only hope is to broaden its therapeutic window through a combination, but that is something that is still years away.

Indeed, it is not just in prostate cancer that the combo idea has legs. Yervoy has been available since 2011 for melanoma on the strength of a fairly modest response rate benefit, and a combination with Bristol’s highly promising anti-PD-1 antibody nivolumab is seen as one way of boosting efficacy while perhaps reducing the Yervoy dose.

ISI Group’s Mark Schoenebaum wasted no time in floating the nivolumab combo as the answer to the lack of Yervoy’s prostate cancer efficacy. But while a combination of these two agents is already recruiting into a phase III melanoma trial, no studies in prostate cancer are under way (Asco preview: Bristol’s PD-1 combo seizes the early limelight, May 16, 2013).

Failed study

In the phase III Yervoy monotherapy trial, study 043, the anti-CTLA-4 antibody prolonged median overall survival – the primary endpoint – by 1.2 months versus placebo, but this was statistically non-significant, with p=0.053. 799 patients with second-line advanced castrate-resistant prostate cancer (CRPC) had been recruited.

Bristol did highlight antitumour activity in terms of one and two-year survival and progression-free survival benefits, but did not disclose whether any of these numerical changes were statistically significant. Yervoy remains in a phase III study (095) in 600 chemotherapy-naive CRPC patients, but this will not read out for a couple of years.

In any case, the company had already expressed tepid enthusiasm over study 043, and analysts had pinned little hope on it. EvaluatePharma consensus data forecast 2018 Yervoy revenue of $1.8bn – entirely in melanoma.

High dose

One of the biggest problems with 043 must have been the 10mg Yervoy dose – over three times higher than the approved melanoma dose of a drug that even at the lower level has notable gastrointestinal side-effects.

This, coupled with the fact that the very advanced patients represented a tough population, makes it remarkable that the study missed significance by such an apparently narrow margin. However, it seems clear that, despite a mechanistic rationale in CRPC and pilot studies showing PSA lowering, Yervoy’s therapeutic window is just too small.

This is where the combination thesis comes in. Beyond the failed 043 study, clinicaltrials.gov lists 10 other Yervoy prostate cancer trials at various stages – some combining it with therapies including Johnson & Johnson’s Zytiga, Dendreon’s Provenge and anti-androgens.

The boost to the CRPC market given by recent entrants like Zytiga and Medivation’s Xtandi likely explain why Bristol wants a piece of the action, and in time Yervoy might find a place alongside other therapeutics. For now, however, the company has to take a step back.

To contact the writer of this story email Jacob Plieth in London at [email protected] or follow @JacobEPVantage on Twitter