Next-Generation PARP Inhibitor AZD5305 Shows Promising Safety Profile and Clinical Activity in Several Cancer Types

Timothy Yap, MBBS, PhD, FRCP

The next-generation highly selective PARP1 inhibitor AZD5305 showed a favorable safety profile and promising clinical activity in comparison with first-generation PARP inhibitors in patients with several different cancer types, according to initial data from the ongoing phase 1/2a modular PETRA trial (NCT04644068) presented at the 2022 American Association for Cancer Research (AACR) Annual Meeting.¹

Results presented at the AACR meeting demonstrated that AZD5305 met the trial’s end point, showing a manageable safety profile for the next-generation drug in 61 patients across daily doses of 10 (n = 8), 20 (n = 19), 40 (n = 17), 60 (n = 10), 90 (n = 3), and 140 mg (n = 4). There were no discontinuations due to AZD5305-related treatment-emergent adverse events (TEAEs) and only 2 patients required a dose reduction at the time of data cutoff. Moreover, 14.8% (n = 9) of patients experienced treatment-related grade 3 or greater TEAEs, including 3 patients in the 10-mg group, 3 in the 20-mg group, 1 patient in the 40-mg group, 2 patients in the 90-mg group, and none in the 60-mg and 140-mg groups.

Sixteen patients in total experienced serious AEs, with the most coming from the 20-mg group at 9 patients. In comparison, there was 5 patients in the 40-mg group who experienced serious TEAEs and just 2 in the 60-mg group, with no patients having serious AEs in the other groups. Two patients were ultimately discontinued from treatment due to other non–AZD5305-related AEs.

The most common AEs of any grade observed in the PETRA study was nausea (34.4%) and anemia (21.3%), with 14.8% of patients having a case of grade 3 or greater anemia. Other notable AEs among the total patient population included neutropenia (18%), with just 6% experiencing grade 3 or higher neutropenia, and thrombocytopenia (18%), with 3.3% of patients having an event of grade 3 or higher. Researchers noted that the rates of nausea and hematological toxicity were considered low and manageable across all doses.

“AZD5305 is a highly potent inhibitor of PARP1 with significant PARP1 DNA trapping activity at doses that showed no PARP2 activity nor binding activity to any other members of the PARP family,” explained Timothy A. Yap, MBBS, PhD, FRCP, in a presentation of the PETRA data. “AZD5305 is highly selective at greater than 500-fold for PARP1 vs PARP2 at the enzyme level, and in cells correlation inhibition in PARP2 knockout cells is equivalent to inhibition in wild-type cells.”

According to Yap, associate professor in the Department for Investigational Cancer Therapeutics, Division of Cancer Medicine, and medical director of the Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, this favorable safety profile remains better than most first-generation PARP inhibitors such as niraparib (Zejula), talazoparib (Talzenna), rucaparib (Rubraca), and olaparib (Lynparza).

Mean fold coverage over target effective concentration was 7.12 to 55.88 with varying doses of AZD5305, in comparison with 0.36 with niraparib, 0.5 with talazoparib, 2.42 with rucaparib, and 3.13 with olaparib. Additionally, rates of gastrointestinal and hematologic toxicities were lower with AZD5305 compared with the first-generation PARP inhibitors as well as the rates of treatment discontinuations and dose reductions due to TEAEs.

“The excellent PK properties enable significantly improved PK and exposure above target compared to first-generation PARP inhibitors,” Yap said. “Robust and durable target engagement was demonstrated across all dose levels.”

Efficacy results from the trial also proved favorable and warranted further study, according to Yap, as out of 40 evaluable patients with measurable disease, 10 had partial responses by RECIST criteria, with 7 confirmed, and 11 patients had stable disease and 19 patients had progressive disease. Moreover, these results were consistent across treatment dose levels, tumor types, and mutation types as evident by changes in target lesion size; responses were also seen independent of prior PARP inhibition exposure. Patients on the trial also had a circulating tumor (ct) DNA response on the first day of the second cycle of AZD5305 treatment with 8 out of 13 measurable patients showing a ctDNA decrease, which included all patients with prostate cancer whose disease had a BRCA2 mutation.

The median duration of treatment was 2.1 months with 19 patients treated for 16 weeks or more. Treatment is still ongoing in 15 PARP inhibitor–naïve patients and 4 patients who had a prior PARP inhibitor.

“I would like to highlight a patient of mine who is a 51-year-old patient who was PARP inhibitor–naïve, platinum-treatment refractory, with BRCA2-mutated ovarian cancer and she was actually the very first patient on this study at (10 mg of AZD5305 every day),” said Yap, when discussing the efficacy data available from PETRA. “She started treatment back in November 2020, and she remains on trial today with a RECIST partial response at nearly 1 year and 5 months.”

The PETRA study has enrolled 61 patients with advanced HER2-negative breast, ovarian, prostate, or pancreatic cancer that had germline or somatic BRCA1/2, PALB2, or RAD51C/D loss-of-function mutations. Patients received AZD5305 every day until disease progression across several dose levels. Eligible patients had to have an ECOG performance score of 0 to 2 and hemoglobin at 9.0 g/dL or greater.

The median age of patients on the trial was 56 years (25-78) with 16 patients 65 years or older. The majority of patients were white (65.6%) and there were 19 patients with ovarian cancer compared to 18 with breast cancer, 12 with pancreatic cancer, and 10 with prostate cancer. In patients with ovarian cancer 4 were platinum sensitive while 14 were resistant or refractory to platinum therapy and 1 patient’s status still being determined. In patients with breast cancer 5 had triple negative breast cancer, 12 were homologous recombination positive, and 1 patient was pending results. Twenty-nine patients had a BRCA2 mutation in their tumor compared to 21 with BRCA1, 7 had PALB2, and 1 with RAD51C.

Enrollment in the 140-mg group is still open. The primary objective of the study is safety and tolerability with secondary objectives including preliminary efficacy and pharmacokinetics (PK) and pharmacodynamics in the tumor and/or blood samples acquired.

_Reference

_{Yap T, Im S, Schram A, et al. PETRA: First in class, first in human trial of the next generation PARP1-selective inhibitor AZD5305 in patients (pts) with BRCA1/2, PALB2 or RAD51C/D mutations. Presented at American Association for Cancer Research Annual Meeting; April 8-13, 2022; Virtual. Accessed April 11, 2022. https://bit.ly/3jsOmgo}