BRCA1/2 are crucial in the homologous recombination repair (HRR) pathway, with loss-of-function (LoF) alterations predicting sensitivity to PARP-inhibitors (PARPi). Whether other HRR-gene alterations confer PARPi sensitivity remains unclear. In the Drug Rediscovery Protocol, patients receive off-label drugs matched to their tumor molecular profile. Here, olaparib efficacy and safety were evaluated in adult patients with treatment-refractory, progressive malignancies harboring LoF alterations in ATM (cohort A) or other HRR-genes including CDK12, PPP2R2A, CHEK1/2, and RAD51B (cohort B). Primary endpoints were clinical benefit (CB: confirmed objective response or stable disease ≥16 weeks) and safety. Pre-treatment biopsies were analyzed by whole-genome sequencing (WGS) for target validation. CB was observed in 8/25 patients (32%) in cohort A (prostate cancer: n = 6, adenoid cystic carcinoma: n = 1, endometrial cancer: n = 1). No effectiveness was seen in patients with colorectal cancer (n = 8). Median progression-free survival (PFS) and overall survival (OS) were 3.4 months (95% CI 1.8-5.3) and 9.2 months (95% CI 5.2-21.3), respectively. In cohort B, the CB rate was 41.7% (10/24) with median PFS and OS of 3.5 months (95% CI 3.4-6.6) and 8.1 months (95% CI 6.6-14.2), respectively. CB was observed in CKD12 (n = 7), RAD51B (n = 2), and CHEK2-altered tumors (n = 1), but not in PPP2R2A (n = 6) or CHEK1-altered tumors (n = 1). No unexpected toxicities occurred. WGS confirmed inclusion target in 84% of tested patients. In conclusion, PARPi sensitivity varies across HRR-genes, indicating that relying solely on an altered common mechanistic pathway is insufficient to predict response. Future studies should target specific HRR-genes to assess subgroup-specific benefits and determine proper use of molecular diagnostics.
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