AstraZeneca Unveils Next-Gen PARP1-Selective Inhibitor AZD5305 to Succeed Lynparza

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AstraZeneca’s PARP inhibitor, Lynparza, rapidly became a blockbuster drug by killing tumor cells through the inhibition of their DNA repair capabilities. However, Lynparza is not a perfect molecule. The British pharmaceutical company is currently launching a potential alternative, hoping it will deliver comparable efficacy without causing its notorious side effects.

At the AACR meeting, AstraZeneca announced early data on AZD5305, its next-generation PARP1-selective inhibitor, aiming to highlight the drug’s potential to follow up on and improve upon the blockbuster Lynparza.

In a set of abstracts, AstraZeneca presented cases for AZD5305, a drug that entered Phase I clinical trials last December, including early in vivo preclinical data as monotherapy and in combination with standard of care. PARP inhibitors target the DNA damage response (DDR) pathway to effectively prevent tumor cells from self-repairing after damage induced by chemotherapy or targeted therapy. AstraZeneca aims for AZD5305 to succeed Lynparza, offering potentially broader combination therapy options and earlier-line treatment, owing to its higher specificity and expected reduced safety risks.

Lynparza is a PARP1/2 inhibitor whose combination therapy scope is limited due to side effects. Drawing on prior experience with Lynparza, the AstraZeneca team believes that the therapeutic window of AZD5305 will be significantly expanded, including use in combination with full-dose chemotherapy and potentially with AstraZeneca’s growing portfolio of antibody-drug conjugates.

The DDR pathway is an old target for pharmaceutical companies, but it has gained popularity with the advent of PARP inhibitors and may overshadow their frustrating safety profiles. AstraZeneca is conducting clinical research on another enzyme in the DDR pathway—the WEE1 inhibitor AZD1775, which has shown overall survival (OS) benefits for pancreatic cancer patients and is also considered a follow-up drug to Lynparza. As early as August 2019, in a small-scale study involving 32 pancreatic cancer patients, the candidate drug extended OS by 22 months and progression-free survival by 9 months.

Susan Galbraith, Senior Vice President and Head of Oncology R&D at AstraZeneca, stated: “We believe this will represent a cleaner safety profile, more potent cytotoxicity, and broader binding capacity in the clinical setting. This will enable us to advance the compound into early-stage development and combine it with a range of different drugs.”

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AstraZeneca unveils next-gen PARP inhibitor, looking to follow up on success of first-gen success story Lynparza