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Saruparib showed promising tumor growth inhibition in preclinical models of breast, ovarian, pancreatic, and prostate cancer harboring HRR-deficiency mutations.
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Selective PARP Inhibitor Improves Survival in Breast Cancer Trial

Saruparib has higher selectivity for PARP1, improving safety and tolerability compared to existing first-gen PARP inhibitors

American Association for Cancer Research
Published:Apr 09, 2024
|3 min read
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SAN DIEGO, CA — Saruparib, a selective inhibitor of poly-ADP ribose polymerase 1 (PARP1), demonstrated a promising objective response rate and progression-free survival in patients with certain homologous recombination repair (HRR)-deficient breast cancers, according to results from the Phase 1/2 PETRA trial.

Although blocking the enzyme PARP1 may be sufficient to prevent DNA repair in HRR-deficient tumors, all PARP inhibitors currently approved by the U.S. FDA block both PARP1 and PARP2, which can limit utility because of toxicity, explained Timothy A. Yap, MBBS, PhD, professor of Investigational Cancer Therapeutics and vice president and head of clinical development in the Therapeutics Discovery Division at The University of Texas MD Anderson Cancer Center.

“When we were developing first-generation PARP inhibitors, we weren’t able to increase the doses above a certain threshold because of toxicity,” Yap said. “By designing selective PARP1 inhibitors, we have a great opportunity to improve safety, tolerability, pharmacokinetics, pharmacodynamics, efficacy, and combinability with other therapies.”

Promising antitumor action of Saruparib

Saruparib, a PARP1-specific inhibitor, showed promising tumor growth inhibition in preclinical models of breast, ovarian, pancreatic, and prostate cancer harboring HRR deficiency mutations. Because saruparib was less toxic than other PARP inhibitors, it could be given at higher doses.

“The properties of saruparib enable patients to reach high drug pharmacokinetic exposure levels and pharmacodynamic target engagement,” Yap said. “This means that patients may be able to stay on the optimal dose for a longer duration due to fewer dose interruptions and reductions, which may ultimately improve efficacy.”

The PETRA trial

PETRA is a multicenter Phase 1/2 clinical trial evaluating the safety, tolerability, and efficacy of saruparib in 306 patients with previously treated (including less than one prior PARP inhibitor in the dose escalation phase and PARP inhibitor-naive breast cancer patients in the dose expansion phase) HRR-deficient breast, ovarian, pancreatic, or prostate cancer. Patients had tumors with mutations in one of five HRR genes: BRCA1, BRCA2, PALB2, RAD51C, or RAD51D.

Patients were treated at doses ranging from 10 to 140 mg of saruparib daily; 60 mg daily was chosen as the recommended dose for further clinical development. Among the 31 breast cancer patients treated with 60 mg saruparib, the objective response rate was 48.4 percent, the median duration of response was 7.3 months, and the median progression-free survival was 9.1 months.

Adverse effects of saruparib treatment

In the cohort of 141 patients who received the 60 mg dose across all cancer types, adverse events were observed in 92.2 percent of patients and 12.1 percent of patients experienced a serious adverse event. Adverse events related to saruparib were observed in 76.6 percent of patients, and 2.1 percent of patients had a serious adverse event related to the drug; some 3.5 percent of patients discontinued treatment due to adverse events related to saruparib.

Yap noted that the adverse events profile from this Phase 1/2 trial of heavily pretreated patients compared favorably to those from Phase 3 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 said.

Pharmacokinetic analyses showed that, at all dose levels, patients maintained higher blood concentrations of saruparib than typically observed with other PARP inhibitors. At the molecular level, saruparib inhibited around 90 percent of PARP activity in tumor tissue collected from biopsies.

“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 said.

- This press release was originally published on the American Association of Cancer Research website