Broadening the PARP playing field

How the PARP field is mapping out new synthetic lethality plays

With its latest clinical win for Lynparza, AstraZeneca is leading the field in stretching the use of PARP inhibitors beyond tumors that carry BRCA mutations. The results highlight one piece of a broader strategy companies are taking to leverage synthetic lethality to extend the reach of the first generation of PARP inhibitors.

On Feb. 26, AstraZeneca plc and partner Merck & Co. Inc. announced that Lynparza olaparib met the primary endpoint in the Phase III POLO trial as maintenance therapy in first-line metastatic pancreatic cancer patients who harbor germline BRCA (gBRCA) mutations.

Metastatic pancreatic cancer has been an intractable disease, with most agents having failed in the clinic in the last decade and only one showing a benefit -- Celgene Corp.’s Abraxane nab-paclitaxel.

The promise of Lynparza as a maintenance therapy in the setting is that it could allow patients who are stable on chemotherapy to take a break from platinum agents, avoiding the cumulative toxicity that comes with long-term exposure. If approved, Lynparza would be the first agent targeted to a molecular subgroup of pancreatic cancer patients.

While the Lynparza results may directly apply to only the 4-7% of pancreatic cancer patients who harbor gBRCA mutations, they reflect a major piece of the strategy that AZ and Merck are using to extend the drug’s reach -- identifying gBRCA-positive patient subpopulations in additional tumor types.

Together, gBRCA mutations and PARP inhibition hinder DNA damage repair, triggering a synthetic lethal interaction that boosts tumor cell killing. But it’s highly likely that mutations in other genes could similarly blunt DNA repair, which means that if companies can find those biomarkers they can expand the use of their PARP inhibitors.

Similarly, finding other mechanisms that synergize with PARP inhibition can allow the drugs to be used in more settings, and in some cases earlier settings within the approved indications.

“We’re moving beyond BRCA.”

Greg Rossi, AstraZeneca

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