Abstract 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.
Spiekman et al. (2025) studied this question.