Surprisingly broad Lynparza approval levels the playing field

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Courtesy of the Solo-2 trial Lynparza had already shown itself to be on a par with Tesaro’s Zejula, so the big surprise of its US approval yesterday in maintenance ovarian cancer treatment was how broad its new label is.

Until now Zejula had held the upper hand thanks to its maintenance label in all-comers, and Lynparza was seen as approvable in a subset of patients with germline BRCA mutations. Yet the Astra drug has got the green light in all-comers too, backed by mediocre results from a phase II trial, heaping more pressure on Tesaro and its bloated valuation.

That market cap, of course, to some extent bakes in a takeover, something that so far has been all talk and no action, and which could now be seen as less likely. Tesaro fell 3% yesterday, but is still valued at $5.9bn.

Broad label

Lynparza had been the first Parp inhibitor to gain approval, for fourth-line ovarian cancer treatment, but Zejula soon became the most popular one thanks to its broad maintenance label, backed by the Nova trial (Tesaro wins one battle, but Parp war awaits, March 28, 2017).

Astra’s Solo-2 study matched or even slightly bettered this – but only in gBRCA patients. The PFS benefit Lynparza had shown in all-comers in the smaller Study 19 was far less impressive, at just 8.4 versus 4.8 months for placebo, but nevertheless the FDA has now granted it maintenance approval in all-comers.

The duo looks likely soon to be joined by Clovis’s rival, Rubraca, which in Ariel3 matched Zejula in all-comers, and now looks headed for additional US approval in this setting too (Ariel3 puts Rubraca on Parp with Zejula, June 19, 2017).

Across-trial comparisons of Parp inhibitors in maintentance ovarian cancer treatment
Zejula Lynparza* Rubraca
BRCA mutant**
mPFS (mth) 21.0 vs 5.5 19.1 vs 5.5 16.6 vs 5.4
Hazard ratio 0.26 0.30 0.23
p value <0.0001 <0.0001 <0.0001
BRCA wild type or all-comers
mPFS (mth) 9.3 vs 3.9^ 8.4 vs 4.8^^ 10.8 vs 5.4^^
Hazard ratio 0.45 0.35 0.36
p value <0.0001 0.0001 <0.0001
Notes: *Lynparza BRCA mutant data from Solo-2, all-comer data from Study 19; **Nova (Zejula) and Solo-2 looked specifically at gBRCA mutants, Ariel3 (Rubraca) was in somatic and germline mutations; ^BRCA wild-type patients; ^^all-comers.

The sellside has been quick to leap to the two biotech groups’ defence. Stifel analysts, who have a buy rating on Clovis, called Ariel3 significantly more compelling than Study 19, which is all that Astra can use to market Lynparza in all-comers; Clovis is capitalised at $3.4bn – significantly below Tesaro.

Leerink, covering Tesaro, also made much of Astra’s lack of phase III data in non-gBRCA patients, and somewhat optimistically called Lynparza’s approval a “clearing event ... which will allow investors to focus on [Tesaro’s] longer-term potential in the Parp inhibitor and I-O space”.

Even split?

Crucially, however, Leerink cut its rating on Tesaro, admitting that Zejula, Lynparza and Rubraca would now split the market near-evenly. Investors might well wonder whether, after all that has been said about differences between the Parps, the FDA has basically decided that these drugs are much of a muchness.

Astra might argue that the PFS differences between Study 19 and Solo-2 come down to a switch from Lynaprza capsules to tablets, and yesterday marked the first approval for the latter formulation, with capsules now being phased out for all Lynparza uses. Tesaro still retains a possible advantage by having the only once-daily Parp.

There is also the puzzling deal Astra did with Merck & Co, since this appeared to give up much of Lynparza's future upside. This might have been driven by the need for the UK group to have some kind of poison pill in place after last month’s failure of its all-important Mystic trial.

Attention now turns to September’s Esmo meeting, where full data will be presented from Ariel3, as well as updated results from Tesaro’s Topacio trial of Zejula plus Keytruda in triple-negative breast and platinum-resistant ovarian cancers, and the Avanova trial of Zejula plus Avastin.

While Esmo data will be scrutinised for additional signals, it seems that the maintenance therapy setting just turned into a battle over subtle nuances.

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobPlieth on Twitter

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