A phase 2 study of olaparib in IDH1 and IDH2 mutant advanced chondrosarcomas and other solid tumors.

3087 Background: Pre-clinical data have shown that mutations in isocitrate dehydrogenase (IDH) 1 and 2 can lead to a “BRCAness” phenotype by impairing homologous recombination (HR) repair. Olaparib, a PARP inhibitor effective in BRCA-mutated cancers such as ovarian, prostate, pancreas and breast cancer, may also be effective in IDH1/2 mutant solid tumors. IDH1/2 mutations are frequently present in gliomas and cholangiocarcinomas but also in other solid tumors, such as chondrosarcomas, and melanomas. This study evaluated the efficacy of olaparib in treating advanced IDH1/2 mutated solid tumors other than cholangiocarcinoma and gliomas. Methods: NCI 10129 was a 3-arm, open-label Phase II clinical trial performed in the NCIExperimental Therapeutics Clinical Trials Network (ETCTN) evaluating olaparib 300 mg twice daily for IDH mutated solid tumors refractory to standard treatment. Patients with solid tumors, excluding cholangiocarcinoma and glioblastoma, were enrolled in cohort 3 of the Phase II trial. The primary endpoint was the overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: From March 2019 until January 2024, a total of 26 patients with IDH1/IDH2-mutant tumors were enrolled in the study across 10 sites. Of these, 14 (53%) had chondrosarcomas, with 5 (35%) being dedifferentiated. Following, the most prevalent histologies were gastrointestinal adenocarcinomas (4, 15%), other sarcomas (3, 12%) and other tumors (5, 19%). Most tumors had IDH1 mutations (n = 20, 77%), with R132C (n = 12, 60%) being the most common substitution. The median age was 62 years (range 43-78), and 18 (69%) participants were male. Patients had received a median of 1.5 prior line of therapy (0-9). After a mean follow-up time of 8.6 months (0.8-62.6), no objective responses were seen, leading to the closure of enrollment. The median PFS was 2 months (95% CI 1.8-2.2), and the median OS was 7.5 months (95% CI 1.3-13). Only two patients had a clinical benefit, defined as PFS > 6 months. Olaparib was tolerable, with most adverse events scored as grades 1-2. Conclusions: Olaparib did not demonstrate activity in IDH-mutant chondrosarcomas and other solid tumors. This study underscores the remarkably poor outcome associated with IDH mutant tumors, emphasizing the urgent need for additional therapeutic options. Further evaluation of the correlative data, including assessment of HR proficiency, 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: NCT03212274 .