AACR 2022: Next-generation PARP1-selective inhibitor demonstrates promising clinical activity with a favourable safety profile

11 Apr 2022
AACR 2022: Next-generation PARP1-selective inhibitor demonstrates promising clinical activity with a favourable safety profile

Results from the Phase I/IIa PETRA trial showed that AZD5305, a potent and highly selective next-generation PARP1 inhibitor and trapper, achieved maximal target engagement and promising clinical activity with a favourable safety profile.

The targeted therapy demonstrated significantly improved pharmacokinetics and exposure above target than could be achieved with first-generation PARP inhibitors.

The data was presented at the American Association for Cancer Research (AACR) Annual Meeting 2022.

In addition to blocking PARP enzymatic activity, first-generation PARP inhibitors trap PARP1 and PARP2 — two repair proteins that activate the DDR pathway — to the sites of DNA damage to prevent DNA repair and to selectively kill cancer cells.

However, a growing body of evidence shows that only PARP1 inhibition and trapping is required for synthetic lethality in cancers with homologous recombination repair (HRR) deficiency.

“By selectively inhibiting and trapping PARP1, AZD5305 achieved greater antitumor efficacy across select tumour and molecular subtypes, more durable target inhibition and superior tolerability compared to first-generation dual PARP1/2 inhibitors in preclinical models,” Yap said.

“These exciting trial results of AZD5305 demonstrate that we can build on the success of first-generation PARP inhibitors by providing important clinical proof of concept for this innovative strategy. We were able to achieve substantially improved safety, pharmacokinetics, pharmacodynamics and promising efficacy in patients with different molecularly-driven cancers with AZD5305.”

In the first-in-class, first-in-human trial, researchers enrolled and treated 61 patients with advanced breast, ovarian, prostate or pancreatic cancer bearing germline or somatic BRCA1/2, PALB2 or RAD51C/D mutations with AZD5305.

Of the 40 evaluable patients, 10 achieved RECIST partial responses and 11 achieved RECIST stable disease across doses, tumour types and mutation types and were independent of prior PARP inhibitor use.

The most common grade ≥3 TEAE, irrespective of causality, was anaemia (14.8%), followed by neutropenia (6.6%) and thrombocytopenia (3.3%).

Only two patients (3.3%) required a dose reduction after experiencing treatment-related grade 3 neutropenia and grade 1 thrombocytopenia.

At the time of data cutoff, there were no dose-limiting toxicities, treatment-related serious adverse events or treatment discontinuations.

Overall, AZD5305 was well tolerated with low rates of nausea and haematological toxicity compared to first-generation PARP inhibitors.

The drug achieved robust and durable pharmacodynamic target engagement across all dose levels, measured by the inhibition of poly ADP-ribosylation (PARylation), which showed that AZD5305 led to maximal target engagement of at least 90%.

Researchers are currently conducting expansion trials to evaluate the drug’s efficacy in PARP inhibitor-naïve populations and dose escalations of combination therapies, including trastuzumab deruxtecan and datopotamab deruxtecan.

Source: University of Texas M. D. Anderson Cancer Center