The novel poly-ADP ribose polymerase-1 (PARP1)-selective inhibitor saruparib demonstrated early efficacy and a favorable safety profile in patients with homologous recombination repair (HRR)-deficient breast cancer, according to new findings presented by Yap et al at the American Association for Cancer Research (AACR) Annual Meeting 2024 (Abstract CT014).
Background
Previous studies have shown that PARP inhibition may be effective in cancers harboring gene mutations that negatively affect DNA repair—including BRCA1/2 mutations—because these tumors rely on PARP proteins to repair any DNA damage. By inhibiting PARP proteins, these cancer types may be unable to repair their DNA, leading to an inability to replicate and, ultimately, cell death.
While first-generation PARP inhibitors targeting both PARP1 and PARP2 have become the standard of care for certain types of cancers, saruparib is a new-generation oral inhibitor selectively targeting PARP1.
“Saruparib is a first-in-class, highly selective, and potent new generation PARP1-selective inhibitor with a wide therapeutic index,” explained lead study author Timothy Yap, MBBS, PhD, Professor of Investigational Cancer Therapeutics as well as Vice President and Head of Clinical Development in the Division of Therapeutics Discovery at The University of Texas MD Anderson Cancer Center.
Study Methods and Results
In the new phase I/II PETRA trial, researchers assigned a total of 31 patients with HRR-deficient advanced breast cancer to receive the optimal recommended dose of 60 mg of saruparib. Among these patients, 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.
The study included 141 patients who were eligible for safety analysis at a dose of 60 mg of saruparib. The researchers found that just 14.2% of the patients had to reduce their dosages and 3.5% of them had to discontinue saruparib as a result of treatment-related adverse events—the most common of which were anemia, neutropenia, thrombocytopenia, fatigue, and asthenia. They noted that the safety profile in this heavily pretreated patient population compared favorably with phase III data from approved first-generation PARP inhibitors.
Conclusions
The researchers emphasized that the improved safety profile of saruparib could allow for more combinations with other therapies and earlier opportunities to patients with early disease stages.
“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,” Dr. Yap underscored.
The researchers are currently evaluating rational saruparib combination strategies in the phase III trial setting.
Disclosure: The research in this study was funded by AstraZeneca. For full disclosures of the study authors, visit abstractsonline.com.
