Johnson & Johnson’s plan to extend its prostate cancer franchise already looked under threat with the resurgence of its soon-to-be-generic blockbuster Zytiga. Now results of the Spartan study have as good as confirmed how hard it will be for Zytiga’s heir apparent, apalutamide, to carve out a niche here.
The study, being presented this week at the Asco-GU symposium, met its primary endpoint, with apalutamide decreasing the risk of metastases versus placebo in patients with non-metastatic castration-resistant prostate cancer (CRPC). But Zytiga’s move earlier up the treatment cascade, and apalutamide’s failure to extend overall survival significantly, threaten the new agent’s relevance in this fast-changing market.
This is largely down to the ground-breaking, academia-run Stampede study (Esmo 2017 – Academic boffins Stampede over the pharma industry, September 9, 2017). Zytiga had established itself in metastatic CRPC, but after showing a stunning effect in Stampede it secured an EU label extension in metastatic hormone-sensitive prostate cancer (HSPC) too; US approval in this early setting is also sought.
J&J’s problem is that Zytiga could be besieged by generics this year, and its attempt to replace this potentially cheap drug with a novel agent depends on carving out a new treatment niche.
This niche is non-metastatic CRPC – the setting in which apalutamide was tested in Spartan. The new project is also in Titan, a phase III study in metastatic HSPC, but this is not due to read out until 2020.
True, apalutamide does look approvable on the strength of Spartan, which will be a relief to J&J: the event-driven trial originally had a primary completion date of December 2016. Curiously, J&J did not report topline Spartan data before filing apalutamide in the US in October, at the time only saying that results would be presented at an upcoming medical meeting; an approval decision is due by April.
Spartan met its primary endpoint, metastasis-free survival, with a 72% reduction in the risk of metastasis or death with apalutamide versus placebo; patients in the treatment group had a median metastasis-free survival of 40.5 months, compared with 16.2 months in the control group.
Pfizer's rival Xtandi faces a similar battle in prostate cancer, and its study in non-metastatic CRPC, Prosper, also read out at Asco-GU. This showed remarkably similar data: 36.6-month metastasis-free survival versus 14.7 for placebo, and a non-significant numerical benefit in overall survival – just like apalutamide in Spartan.
Both studies raise numerous issues. How relevant is the non-metastatic setting? How accurately can non-metastatic status be diagnosed? Will most patients realistically already have received Zytiga – something Spartan naturally did not envisage? And how important is it that Spartan and Prosper failed to show an overall survival benefit?
The last point might be the most damning, and the design of Spartan brings this failing into stark relief, as patients whose cancer metastasised were subsequently offered open-label Zytiga.
It therefore looks like apalutamide’s extension of metastasis-free survival has simply managed to delay the point at which patients got Zytiga, whereupon they all saw roughly the same survival benefit. Put simply, J&J has created a window for giving an expensive new drug, and delayed the administration of a cheap one, with no meaningful extension in life expectancy.
Undaunted, in summarising the Spartan data at an Asco-GU press briefing, Dr Eric Small, from the University of California San Francisco, said: “These data suggest that apalutamide should now be considered as a new standard of care for men with high-risk non-metastatic CRPC.”
This might well be the case, but it does not get around the fact that the non-metastatic CRPC setting could be a somewhat hard-to-quantify niche. There might be a window of opportunity to give apalutamide before patients need Zytiga, but Zytiga’s earlier use could make this window vanishingly small.
Expectations for apalutamide have already fallen since July, and could now come down further still. EvaluatePharma 2022 sellside consensus currently sits at $1.2bn. J&J needs new blood, and previously said that apalutamide would be one of 12 potential blockbusters in its pipeline (Johnson & Johnson lays out its battle plan, May 18, 2017).
This now looks unlikely, and J&J will be waiting a while to find out if the Titan trial can do anything to salvage the profitability of its prostate cancer franchise.
|Titan||Metastatic HSPC||NCT02489318||Nov 2020|
This is an updated version of an earlier story.