Dr. Timothy Yap on an Effective Therapy for HER2-Negative Breast Cancer

DocWire News spoke with Timothy Yap, MD, PhD, of the MD Anderson Cancer Center, about the PETRA trial, which assessed saruparib, a selective inhibitor of poly(adenosine diphosphate–ribose) polymerase 1 (PARP1). The therapy was effectively used on a cohort of patients with HER2-negative breast cancer with BRCA1, BRCA2, PALB2, RAD51C, or RAD51CD mutations. The results were presented at the American Association for Cancer Research Annual Meeting 2024.

Please provide an overview of the phase 1/2 PETRA trial.

The first in-human, phase 1/2A PETRA trial assessed a PARP1 inhibitor called saruparib, which is highly potent and highly selective for PARP1. During dose escalation, we explored doses from 10 mg all the way up to the highest dose of 140 mg once daily. We found that the drug was safe, well tolerated, and associated with very infrequent dose interruptions, dose reductions, and drug discontinuations. Importantly, we also found that we were able to achieve much higher pharmacokinetic drug exposures, as well as very robust pharmacodynamic target inhibition, with greater than 90% PARylation inhibition.

During dose escalation, we actually saw responses at every dose level. That provided the rationale to proceed to a dose optimization expansion cohort where we focused on HER2-negative breast cancer patients with mutations. There was no limit on prior lines of chemotherapy. Again, what we found while looking at safety, pharmacokinetics, pharmacodynamics, and efficacy was that it was very favorable, especially versus the first-generation PARP1 and PARP2 inhibitors. There was an overall response rate of 48.4% and a median progression-free survival of 9.1 months.

Please describe the mechanism of action of saruparib.

The current approved PARP inhibitors are all PARP1 and PARP2 inhibitors and trappers. We know, though, that to shrink cancers and benefit patients, we really need to focus on PARP1 inhibition. That knowledge provided the rationale to really dial out PARP2 and create this PARP1 selective and potent inhibitor called saruparib. Saruparib is the first-in-class PARP1-selective inhibitor where we have been able to drive drug exposures up safely without the side effects, or the severity of some of the side effects, that we have seen with approved PARP inhibitors.

The hope is that by achieving much greater drug exposures and pharmacodynamic effects, in hitting the target hard enough in a sustained fashion, that we can ultimately achieve much greater efficacy. Potentially, it may also allow us to combine saruparib with other drugs and rational combinations. Currently, we have already moved on to phase 3 clinical trial testing and, in prostate cancer, combining saruparib with new hormonal agents.