The failure of Active Biotech/Ipsen’s tasquinimod in the large 10TASQ10 phase III study in prostate cancer provides a salutary lesson on one of the peculiar pitfalls in cancer drug development: new and highly efficacious agents can be added in later lines of therapy once a trial has begun, masking the effects of a study drug.
This is what seems likely to have occurred with poor old tasquinimod, whose fate was sealed as Medivation/Astellas’s Xtandi, Johnson & Johnson’s Zytiga and Bayer’s Xofigo have been have introduced in patients whose disease has advanced. Active today reported top-line results from the 10TASQ10 study, which showed a solid improvement in progression-free survival, but none on overall survival.
Not enough benefit
The trial enrolled 1,200 pre-chemo metastatic castrate-resistant prostate cancer (mCRPC) patients, who were randomised on a 2:1 ratio to tasquinimod – three doses were tested – or placebo.
The trial's inability to translate PFS into a survival benefit mirrors results seen with a number of high-profile agents in this setting in recent years, which has in most cases been attributed to subsequent use of the new agents across both arms of the study. Nevertheless, for both commercial and regulatory reasons, it is essential to show some sort of OS benefit – even if only a trend – so the decision to discontinue the product comes as little surprise.
The 10TASQ10 study was started in 2010 and reached full enrolment surprisingly swiftly in late 2012. However, 2012 also saw the approvals of the anti-androgens Zytiga and Xtandi, which quickly become standard of care, and together with the approval of Xofigo in 2013 dramatically changed the landscape in this setting.
It seems likely that use of post-progression therapy with one or more of these agents masked any OS benefit for tasquinimod that might have been seen in the absence of these new drugs, although it is important to stress that this has yet to be shown by examination of detailed study data.
Nevertheless, whatever the reason for the failure it provides little consolation for the long-suffering investors in Sweden’s once-leading biotech: its shares fell by over 60% today.
Success hard to come by
Active Biotech’s future now hangs on the success of a phase III multiple sclerosis study with the chemically related compound laquinimod, whose results are due in 2016. Laquinimod has its own chequered history, and is partnered with Teva. At least Active Biotech has a cash reach extending into 2016, but a painful cost-cutting is clearly on the cards.
Tasquinimod was one of several agents that entered phase III at the start of the decade for both pre and/or post-docetaxel mCRPC, most of which failed after achieving approval in other indications. Tasquinimod thus joins a list that includes Takeda’s ortoronel, Oncogenex/Teva’s custirsen, Exelixis’s cabozantinib, Celgene's Revlimid, Sanofi’s Zaltrap, Bristol-Myers Squibb’s Yervoy and dasatinib and Roche’s Avastin in the mCRPC failure bin.
In many cases, these drugs showed the same pattern of an improvement in PFS, while lacking any benefit on OS (Asco-GU – Orteronel post-mortem shows harsh reality of post-Xtandi world, January 31, 2014).
One agent from this 2010 cohort has, however, yet to yield data. That is Bavarian Nordic’s Prostvac, which was recently partnered with Bristol-Myers Squibb and is due to render data next year.
Perhaps wisely, few companies have decided to target the mCRPC space in recent years. Those that have, such as J&J with its Zytiga-follow up JNJ56021927/ARN-509, probably have some sort of cunning commercial plan. One that has made a move is the little-known Czech company Sotio, which has launched a phase III study with its dendritic cell vaccine, DCVAC.
There are, however, a host of trials with the three newly approved products, seeking to gain marketing advantage or move them into earlier-line use, including in non-metastatic disease. Xtandi looks likely to achieve this: two weeks ago data from the Strive phase II study, which included non-metastatic and metastatic patients, showed a large benefit. Median PFS for Xtandi reached 19.4 months versus 5.7 months for bicalutamide.
The lessons from tasquinimod and other agents in mCRPC are perhaps to pick your indications carefully. It is difficult to show an OS benefit in cancer when a more efficacious agent becomes used in a later line of therapy.