Saruparib, a selective inhibitor of poly-ADP ribose polymerase 1 (PARP1), has demonstrated a promising objective response rate and progression-free survival in patients with certain homologous recombination repair (HRR)-deficient breast cancers. These findings come from the phase I/II PETRA trial, which were presented at the American Association for Cancer Research (AACR) Annual Meeting 2024.
The PETRA trial is a multicenter phase I/II clinical trial that evaluated the safety, tolerability, and efficacy of saruparib in 306 patients with previously treated HRR-deficient breast, ovarian, pancreatic, or prostate cancer. Patients' tumors had mutations in one of five HRR genes: BRCA1, BRCA2, PALB2, RAD51C, or RAD51D. The study included patients who had received one prior PARP inhibitor in the dose escalation phase and PARP inhibitor-naive breast cancer patients in the dose expansion phase.
Improved Safety Profile
According to Timothy A. Yap, MBBS, PhD, professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, existing PARP inhibitors block both PARP1 and PARP2, potentially limiting utility due to toxicity. Saruparib, being PARP1-specific, aims to improve safety and tolerability.
"By designing selective PARP1 inhibitors, we have a great opportunity to improve safety, tolerability, pharmacokinetics, pharmacodynamics, efficacy, and combinability with other therapies," said Yap.
Preclinical models showed that saruparib inhibited tumor growth in breast, ovarian, pancreatic, and prostate cancer with HRR deficiency mutations. Saruparib's lower toxicity allowed for higher doses to be administered.
Clinical Trial Results
Patients in the PETRA trial were treated with saruparib at doses ranging from 10 to 140 mg daily. The recommended dose for further clinical development was determined to be 60 mg daily. Among the 31 breast cancer patients treated with 60 mg saruparib, the objective response rate was 48.4%, the median duration of response was 7.3 months, and the median progression-free survival was 9.1 months.
In the cohort of 141 patients who received the 60 mg dose across all cancer types, adverse events were observed in 92.2% of patients, with 12.1% experiencing a serious adverse event. Adverse events related to saruparib were observed in 76.6% of patients, and 2.1% of patients had a serious adverse event related to the drug. Only 3.5% of patients discontinued treatment due to adverse events related to saruparib.
Manageable Safety Profile
Yap noted that the adverse events profile from this phase I/II trial compared favorably to those from phase III trials testing other PARP inhibitors in treatment-naïve patients. "The low rate of dose reductions observed with saruparib suggests a very manageable safety profile that we believe will enable patients to stay longer at the optimal dose and therefore maximize the opportunity for long-term benefit," Yap stated.
Pharmacokinetic analyses showed that patients maintained higher blood concentrations of saruparib than typically observed with other PARP inhibitors across all dose levels. At the molecular level, saruparib inhibited approximately 90% of PARP activity in tumor tissue collected from biopsies.
Implications for Treatment
"The excellent safety and tolerability profile, along with the favorable pharmacokinetic and pharmacodynamic properties, may enable patients to remain on saruparib treatment with sustained maximal target engagement and limited dose reductions or discontinuation," Yap concluded. The study's limitations include its single-arm design and small sample size.
