Journal: Cancer
Phase II, biomarker-selected, multi-arm trial evaluating olaparib-based combinations in molecularly defined, histology-agnostic solid tumors.
Design:
- Patient assignment: based on next-generation sequencing
- Cohort 1: DDR-mutated tumors → olaparib monotherapy
- Cohort 2: DDR-mutated tumors → olaparib + ATR inhibitor ceralasertib
- Cohort 3: PI3K–AKT pathway–altered or ARID1A-mutant tumors → olaparib + AKT inhibitor capivasertib
- Primary endpoint: 16-week overall response rate (RECIST 1.1)
Population:
- Total treated: 66 patients
- Olaparib alone: 26 patients
- Olaparib + ceralasertib: 24 patients
- Olaparib + capivasertib: 16 patients
Efficacy:
- Overall response rate (all arms): 6.1%
- Clinical benefit rate (CR+PR+SD): 31.2%
- Median duration of clinical benefit: 11 months
- Notable signal: in seven patients with platinum- and prior PARP-resistant high-grade serous ovarian carcinoma treated with olaparib + ceralasertib:
- Partial response: 1 patient
- Stable disease: 4 patients
- Median duration of benefit in this subgroup: 10 months
Safety:
- No unexpected toxicities; tolerability consistent with known profiles of the agents.
Conclusion:
- The trial did not meet its primary endpoint.
- DDR or homologous recombination repair defects alone are insufficient as universal, histology-agnostic predictors of benefit from olaparib, either as monotherapy or combined with ATR or AKT inhibition.