AACR: AstraZeneca next-gen PARP inhibitor gives 'bang for your buck' over firstcomers

The University of Texas MD Anderson Cancer Center’s Timothy Yap, M.D., doesn’t know why AstraZeneca’s PARP inhibitor saruparib seems to be spurring responses in patients who have previously not had much luck with the drug class.

“It is something that I've been scratching my head on ever since we presented the case, two years ago at this meeting. One could argue that we have a better drug here, that we're achieving much higher drug exposures in patients,” Yap said during a press conference at the American Association for Cancer Research annual meeting on Monday morning. He serves as a professor of investigational cancer therapeutics and vice president and head of clinical development in the cancer center's therapeutics discovery division.

Approved PARP inhibitors include AstraZeneca and Merck & Co.’s Lynparza, pharmaand’s Rubraca and GSK’s Zejula.

The first-in-human results for saruparib, presented by Yap from the phase 1/2a PETRA module trial, showed an objective response rate of 48.8% in the 31 evaluable patients at the target dose. Median progression-free survival was 9.1 months.

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The main goal of the study was safety and tolerability, with secondary goals providing an early look at efficacy. Patients in the part A dose escalation group had advanced, metastatic breast cancer and had previously tried at least three prior lines of therapy. Forty-five percent had prior treatment with a PARPi and/or chemotherapy.

The part B dose expansion featured patients with HER2-negative disease who had not previously received a PARP inhibitor. Most had BRCA mutations, and there was no limit on the number of prior chemotherapy treatments.

Yap explained that saruparib is highly selective for PARP1. The oral therapy has “superior” pharmacokinetic and pharmacodynamic properties and efficacy when compared with approved PARP inhibitors, according to the presentation.

“The approved PARP inhibitors we know benefit patients. But these are all PARP1 and PARP2 inhibitors and in the patients that we've already been treating … we know that there are associated toxicities,” Yap said, noting gastrointestinal toxicities and fatigue as the main issues. “We also know that PARP1 inhibition alone is all you need to really shrink cancers and to benefit patients and lead to efficacy. And that really provides a whole rationale to really dial out the PARP2.”

That’s why saruparib was developed. “What we have seen on trial, to summarize, is we really get bang for your buck," Yap said. Patients may also be able to stay on treatment longer at an optimal dose, meaning improved efficacy.

The PETRA trial also showed durable responses with the 60-mg dose in a heavily pretreated population of patients. That’s the dose that will be taken forward, in line with the FDA’s Project Optimus, which asks drug developers to test a wider range of doses early on to determine the safest and most efficacious dose.

Overall, the study had 141 patients who were evaluable for a safety analysis on the 60-mg dose. The safety data were consistent with the earlier 2022 data release, when fewer patients were in the trial with less follow-up time, according to Yap. In this group, 14.2% of patients had to reduce dosage, and 3.5% stopped altogether due to adverse events like anemia, neutropenia, thrombocytopenia, fatigue and asthenia.

The trial did, however, show that the 140-mg dose was not tolerable. Four out of six patients in that cohort had dose interruptions or reductions. But up to 60 mg was tolerated, so this was chosen as the preferred go-forward dose. 

Yap said the safety profile in the heavily pretreated population was in line with the approved PARP inhibitors.

A phase 3 test is ongoing with the 60-mg dose in a test called EvoPAR-Prostate01. The therapy will be tested in combination strategies.