Lyparza sets Parp inhibitors a new target

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Astrazeneca’s Lynparza led the surprising resurgence of Parp inhibitors in ovarian cancer, and today’s hit in breast cancer, the first for a Parp inhibitor, raises the stakes further for competitors in this drug class.

In particular, Pfizer/Biomarin’s talazoparib is being studied for breast cancer as its primary indication, with readout expected soon. Data from Tesaro’s Bravo trial are also due this year. Investors will look for positive readacross from the Lynparza data, and full data from Astra will be awaited keenly to see just how high the bar has been set.

For now all the UK firm has revealed is that Lynparza met the Olympiad study’s primary endpoint of progression-free survival versus chemotherapy. The trial recruited 302 patients with Her2-negative breast cancer with germline Brca mutations, and full data are being held back for a medical meeting.

While no unexpected safety issues have been reported, investors will look to overall survival – an Olympiad secondary endpoint – as an important efficacy measure. Astra stock was up 2% in early trade today on hopes that the Olympiad data would swiftly result in Brca-mutated breast cancer being added to Lynparza’s label.

Validating Brca

The hope for competitors is that Astra has again demonstrated that selecting patients whose breast cancer is driven by Brca mutations yields a population that can be targeted by Parp inhibitors.

However, mechanistic subtleties are starting to differentiate the various Parp inhibitors. And in December Abbvie’s veliparib failed to improve progression-free or overall survival in the phase II Brocade breast cancer study; a phase III trial, Brocade 3, is ongoing, in addition to studies in lung and ovarian cancers.

Selected trials of Parp inhibitors in breast cancer
Endpoints
Project Company Study Primary Secondary Trial ID Data timeline
Lynparza Astrazeneca Olympiad 302 gBrca-positive pts PFS OS and others NCT02000622 PFS endpoint met
Talazoparib Pfizer/Biomarin Embraca 429 gBrca-positive pts PFS OS and others NCT01945775 Early 2017
Niraparib Tesaro Bravo 306 gBrca-positive pts PFS OS NCT01905592 2017
Veliparib Abbvie Brocade 3 500 gBrca-positive pts* PFS OS and others NCT02163694 2018
Rubraca Clovis Rio** 81 TNBC or Brca-positive pts ORR Biomarker-based ISRCTN92154110 NA
Ruby** 41 somatic Brca-mutated pts (w/o gBrca) ORR PFS, OS and others NCT02505048 NA
Note: *Earlier Brocade trial failed; numerous investigator-sponsored veliparib trials are ongoing. **Investigator-sponsored trials.

With Lynparza and Clovis’s Rubraca approved for ovarian cancer – Tesaro’s niraparib faces an FDA action date here on June 30 – carving out additional indications has become important for the competition.

Only Pfizer’s talazoparib has breast cancer as its lead indication, however. Its Embraca trial reads out early this year, likely before Tesaro’s Bravo study.

A positive hit in Bravo would add fuel to Tesaro takeover speculation. Breast cancer accounts for 20% of niraparib’s 2022 sellside consensus sales forecast of $1.9bn, according to EvaluatePharma, so clearly Bravo is important in crystallising the company’s value.

It is interesting that Rubraca is the only one of the leading Parp inhibitors not to be studied in breast cancer by its originator. Two phase II trials, Rio and Ruby, are being run in this setting by Cancer Research UK and the French group Unicancer respectively.

If Astra’s Olympiad data will be seen as having a positive readacross for the whole Parp class, one aspect that will make comparisons easier than normal is that the phase III studies have a broadly similar design – looking at Brca-mutated breast cancer, and measuring progression-free survival as the primary endpoint.

That said, with positive data under Lynparza’s belt, the pressure on others to perform just got greater.

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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