Randomized phase 2 trial of a PARP inhibitor TSL-1502 in germline BRCA-mutated, HER2-negative locally advanced/metastatic breast cancer.

TSL-1502 is a glucuronide prodrug of a PARP inhibitor, designed to increase target specificity and reduce toxicity, evaluated in patients carrying germline BRCA1 or BRCA2 variants.

Glucuronide prodrug strategies aim to improve the target specificity of PARP inhibitors and reduce their toxicity, but had not previously been evaluated clinically. This randomised, open-label phase 2 study, run at 28 sites in China (NCT05420779), enrolled 63 women aged 18 to 75 years with HER2-negative locally advanced or metastatic breast cancer and a germline BRCA variant, randomised 2:2:1 to TSL-1502 350 mg once daily, TSL-1502 500 mg once daily, or investigator's choice of chemotherapy (eribulin, capecitabine or vinorelbine). Objective response rates assessed by an independent review committee were 36.0% (95% CI 18.0-57.5), 55.6% (95% CI 35.3-74.5) and 40.0% (95% CI 12.2-73.8), with median progression-free survival of 5.6, 8.8 and 9.2 months and overall survival of 17.4 months, not reached, and 19.8 months. Grade 3 or higher treatment-related adverse events occurred in 60.0%, 59.3% and 80.0% of patients, with anaemia predominating on TSL-1502 and neutropenia on chemotherapy, and no treatment-related deaths.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The higher response rate in the 500 mg arm should not obscure that its progression-free survival remains below that of the chemotherapy arm (8.8 versus 9.2 months), with very wide confidence intervals and a control arm of about ten patients: a randomised phase 2 of this size supports no formal comparison. The relevance for us lies elsewhere, in confirming that germline BRCA status remains the mandatory entry point for any therapeutic development in this setting, which argues for early rather than deferred germline testing. The toxicity question, the central rationale for the prodrug, is not settled either, with grade 3 or higher events still close to 60%.

Analysis by Dr Thibaut Benquey