AZD5305 More Tolerable than Earlier PARP Agents

Data from a phase I/IIa clinical trial of AZD5305 (AstraZeneca), a first-in-class selective PARP1 inhibitor, show improved safety and tolerability compared with first-generation PARP1/2 inhibitors, as well as greater tumor control. Findings from the global study, dubbed PETRA, were presented during the American Association for Cancer Research Annual Meeting 2022 in New Orleans, LA, held April 8–13.

The first-generation PARP inhibitors niraparib (Zejula; GSK), talazoparib (Talzenna; Pfizer), rucaparib (Rubraca; Clovis Oncology), and olaparib (Lynparza; Merck) are approved for several indications. All target both PARP1 and PARP2, leading to the death of cancer cells deficient in homologous recombination repair (HRR). However, “only PARP1 inhibition is required for synthetic lethality in HRR-deficient settings,” explained Timothy Yap, MBBS, PhD, of The University of Texas MD Anderson Cancer Center in Houston, who presented the findings. Studies have shown that PARP2 is needed for erythropoiesis, Yap noted, and blocking it could cause the hematologic toxicities often seen with PARP1/2 inhibitors.

Yap's team hypothesized that a highly selective PARP1 inhibitor would offer an improved tolerability profile, greater target inhibition, and improved efficacy.

Researchers enrolled 61 patients in the trial who had advanced/metastatic ovarian cancer, HER2-negative breast cancer, pancreatic cancer, or prostate cancer with a loss-of-function mutation in BRCA1/2, PALB2, or RAD51C. Patients were eligible if they hadn't received more than one PARP inhibitor, regardless of sensitivity to platinum-containing agents. All participants received one of six different doses of AZD5305, ranging from 10 mg to 140 mg.

“The emerging safety profile for AZD5305 is highly favorable compared with the first-generation PARP inhibitors across all key parameters,” said Yap. There were no treatment discontinuations and no dose-limiting toxicities or serious adverse events; only 3% of patients receiving AZD5305 had a dose reduction compared with up to 53% for first-generation PARP inhibitors. The most common side effects of AZD5305 were nausea, anemia, constipation, and neutropenia, nearly all of which occurred less frequently than with approved PARP1/2 inhibitors.

Of the 40 patients evaluable for efficacy, 10 had partial responses, 11 had stable disease, and 19 experienced progressive disease after a median of 2.1 months, Yap reported. Reponses were seen across all dose levels, tumor types, and mutation types and were independent of prior PARP inhibition.

Yap noted that circulating tumor DNA levels decreased for eight of the 13 patients who had it measured; the response was particularly high in the five patients with prostate cancer in this group—all of whom had decreases of at least 50%. That finding, said Yap, was “particularly impressive” and should be further evaluated as a marker of efficacy.

The drug has “a huge therapeutic index and very little toxicity,” said study discussant Patricia LoRusso, DO, PhD, of the Yale School of Medicine in New Haven, CT. As such, AZD5305 might have value in preventing disease in high-risk patients, including “young women who are BRCA-mutant or have a mutation or defect in homologous recombination and who still want to bear children” because it might delay oophorectomies and mastectomies.

Researchers are continuing to test AZD5305 in PARP inhibitor–naïve patients and testing it with the HER2 antibody drug–conjugate (ADC) trastuzumab deruxtecan (Enhertu; AstraZeneca) and the TROP2-directed ADC datopotamab deruxtecan (AstraZeneca/Daiichi Sankyo).

“Would combination therapy strategies enhance efficacy and duration [of response]?” wondered LoRusso. “Dr. Yap's combination data will hopefully be presented soon and help to answer that question.” –Natalie DiDomenico

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