For cancers that harbor gene mutations that weaken DNA repair, poly-ADP ribose polymerase (PARP) is like a crutch. It ensures that these cancers can keep DNA repair going well to survive. But what if the crutch could be kicked away? That’s the possibility behind the development of PARP inhibitors. They’re crutch kickers that leave susceptible cancers unable to replicate.
High on the list of susceptible cancers are homologous recombination repair (HRR)-deficient cancers, which include breast ovarian, or pancreatic cancers that harbor germline or somatic BRCA1/2, PALB2, or RAD51C/D mutations. And high on the list of PARP inhibitors, in terms of safety and effectiveness, are PARP1-selective inhibitors. Both of these “highs” figure in the PETRA trial. It is a Phase I/II trial in which a PARP1-selective inhibitor, saruparib, is being evaluated in patients with HRR-deficient cancers.
Encouraging results from this trial were presented at the American Association for Cancer Research (AACR) Annual Meeting 2024 by Timothy Yap, MBBS, PhD, of the University of Texas MD Anderson Cancer Center. Specifically, Yap reported that saruparib demonstrated early efficacy and a favorable safety profile in patients with HRR-deficient breast cancers.
A total of 31 patients with advanced breast cancers harboring HRR deficiency mutations received the optimal recommended dose of 60 mg of saruparib. The objective response rate was 48.8% with a median progression-free survival of 9.1 months. The drug had favorable tolerability as well as pharmacokinetic and pharmacodynamic responses.
“Saruparib is a first-in-class, highly selective, and potent new generation PARP1-selective inhibitor with a wide therapeutic index,” Yap said. “The favorable safety profile of saruparib together with the low dose-reduction rate compared to approved PARP inhibitors may allow patients to remain on treatment longer at an optimal dose, offering maximal pharmacokinetic exposure and pharmacodynamic engagement, which could lead to improved efficacy.”
Saruparib is a new-generation oral inhibitor selectively targeting PARP1, whereas previous PARP inhibitors targeted both PARP1 and PARP2. While these first-generation inhibitors have become the standard of care for certain cancers, the improved safety profile of saruparib could allow for more combinations with other treatments and opportunities to bring the benefits of PARP inhibitors to patients in earlier disease stages.
The trial included 141 patients who were eligible for safety analysis at a 60 mg dose. Of these, only 14.2% had to reduce dosage and just 3.5% had to discontinue treatment due to treatment-related adverse events. The most common adverse events were anemia, neutropenia, thrombocytopenia, fatigue, and asthenia.
According to Yap, the safety profile of this heavily pretreated patient population compared favorably to Phase III data from approved first-generation PARP inhibitors. In follow-up to these findings, rational saruparib combination strategies currently are being tested, including clinical evaluation in the Phase III trial setting, Yap noted.
