Randomized phase 2 trial of a PARP inhibitor TSL-1502 in germline BRCA-mutated, HER2-negative locally advanced/metastatic breast cancer.
In a randomized open-label phase 2 trial of 63 adult women with germline BRCA-mutated, HER2-negative advanced breast cancer, TSL-1502 at 500 mg produced a 55.6% objective response rate, 8.8-month median progression-free survival, and fewer grade ≥3 treatment-related adverse events than investigator-selected chemotherapy numerically, although estimates were imprecise.
Open original publication →What the AI sees
In a randomized open-label phase 2 trial of 63 adult women with germline BRCA-mutated, HER2-negative advanced breast cancer, TSL-1502 at 500 mg produced a 55.6% objective response rate, 8.8-month median progression-free survival, and fewer grade ≥3 treatment-related adverse events than investigator-selected chemotherapy numerically, although estimates were imprecise.
Research significance
The trial provides evidence that the glucuronide PARP-inhibitor prodrug TSL-1502 has antitumor activity and manageable toxicity in adults with germline BRCA-mutated, HER2-negative advanced breast cancer; it remains an inference—not demonstrated here—that prodrug targeting improves therapeutic index over conventional PARP inhibitors or that these findings apply to pediatric or adolescent cancers.
Source abstract
Glucuronide prodrug strategies may enhance target specificity and reduce the toxicity of PARP inhibitors, but no clinical evaluation has been performed. We evaluated TSL-1502, a novel glucuronide prodrug of a PARP inhibitor, in a randomized, open-label, phase 2 study at 28 sites in China (NCT05420779). Eligible patients were women aged 18-75 years with HER2-negative locally advanced or metastatic breast cancer and germline BRCA mutations. Patients were assigned randomly (2:2:1) to receive TSL-1502 at 350 mg or 500 mg once daily or the investigator's choice of chemotherapy (eribulin, capecitabine, or vinorelbine) in 3-week cycles. Sixty-three patients were enrolled between August 18, 2022, and March 5, 2024. According to the Independent Review Committee assessment, the objective response rates were 36.0% (95% CI, 18.0-57.5) in the 350 mg group, 55.6% (95% CI, 35.3-74.5) in the 500 mg group, and 40.0% (95% CI, 12.2-73.8) in the chemotherapy group. The median progression-free survival times were 5.6 (95% CI, 4.0-8.2), 8.8 (95% CI, 5.7-not assessable [NA]), and 9.2 (95% CI, 1.38-NA) months, respectively, and the overall survival times were 17.4 months (95% CI, 9.1-NA), not reached (95% CI, 16.9-NA), and 19.8 months (95% CI, 9.2-NA), respectively. Grade ≥3 treatment-related adverse events occurred in 60.0%, 59.3%, and 80.0% of patients, with anemia most common in the TSL-1502 group and neutropenia most common with chemotherapy. No treatment-related deaths occurred. TSL-1502 at 500 mg showed promising antitumor activity and a manageable safety profile, supporting further clinical development.