AACR 2022 | Update on PETRA trial investigating a next-generation PARP1 select inhibitor

Timothy Yap, MBBS, PhD, MRCP, PgDip, University of Texas MD Anderson Cancer Center, Houston, TX, explains results from the Phase I/IIa PETRA trial (NCT04644068) assessing AZD5305, a next-generation PARP1 select inhibitor and trapper, in 61 patients with advanced breast, ovarian, prostate or pancreatic cancers bearing germline or somatic BRCA1/2, PALB2 or RAD51C/D mutations. First-generation dual PARP inhibitors inhibit and trap PARP1 and PARP2, but growing evidence suggests that only PARP1 inhibition is required. By selectively inhibiting and trapping PARP1, AZD5305 achieved greater anti-tumor efficacy across select tumor and molecular subtypes than first-generation dual PARP inhibitors. Specifically, AZD5305 had significantly improved safety, pharmacokinetics, pharmacodynamics and promising efficacy in patients with different molecularly driven cancers. Adverse events observed in the trial were extremely low, with the most adverse events being nausea and mechanism-based haematological toxicity. At the time of cut-off, there were no treatment-limiting toxicities or treatment-related discontinuations. Robust and durable pharmacodynamic target engagement was demonstrated across all dose levels, with maximal target engagement of at least 90%. The success of this trial shows that we can build on the success of approved first-generation dual PARP1/2 inhibitors. Expansion trials are being undertaken to evaluate AZD5305 efficiency in PARP inhibitor naive populations and combination therapies. This interview took place at the American Association for Cancer Research Annual Meeting in New Orleans, LA.