A phase 2 study of the olaparib and AZD6738, an ATM/ATR inhibitor, in isocitrate dehydrogenase (IDH) mutant solid tumors.

3089 Background: Pre-clinical data has shown that mutations in isocitrate dehydrogenase (IDH) 1 and 2 can lead to impaired homologous recombination repair. IDH1/2 mutations are frequently present in gliomas and cholangiocarcinomas but also in other solid tumors, such as chondrosarcomas. AZD6738 is an ATR inhibitor, and Olaparib is a PARP inhibitor. Preclinical evidence showed a synergistic effect of this combination in models with DNA damage repair effects. This study aims to evaluate the efficacy of Olaparib and AZD6738 in treating advanced IDH1/2 mutated solid. Methods: NCI 10222 is an open-label Phase II clinical trial performed in the NCI National Clinical Trials Network evaluating olaparib 300 mg twice daily with AZD6738 160 mg daily for IDH mutated solid tumors refractory to standard treatment. The primary endpoint was the overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: From January 2020 until March 2023, a total of 24 patients with IDH1/IDH2 mutant tumors were enrolled in the study across 8 sites. Of these, 14 (58%) had cholangiocarcinoma, 4 (17%) had chondrosarcomas, and 6 (25%) had other tumors. Most tumors had IDH1 mutations (n = 16, 70%). The median age was 59 years (range 29-83), and 15 (63%) participants were male. Patients had received a median of 3 prior lines of therapy (0-6). After a mean follow-up time of 3 months (0.2-ongoing), no objective responses were seen, leading to the closure of enrollment. The median PFS was 2 months (95% CI 2-4), and the median OS was 7 months (95% CI 3-NE). Only three patients had a clinical benefit, defined as PFS > 6 months, with one patient diagnosed with G1 chondrosarcoma still on treatment with stable disease. Combination of Olaparib with AZD6738 resulted in G3 AE in 9 (38%) patients, leading to 4 (17%) discontinuations. Conclusions: Olaparib with AZD6738 did not demonstrate activity in IDH mutant solid tumors. However, the stability seen in the patient with low-grade tumors could suggest that the effect is restricted to lower-grade tumors, still dependent on IDH mutations. Further evaluation of the correlative data is required to elucidate why pre-clinical evidence suggesting potential efficacy did not translate into clinical benefit in IDH mutant solid tumors. Clinical trial information: NCT03878095 .