Phase II EVOLVE Trial: Genomic Mechanisms of Resistance to PARP Inhibitors
Posted: Wednesday, July 22, 2020
According to results from the multicenter, single-arm phase II EVOLVE study published in Clinical Cancer Research, the combination of the VEGFR inhibitor cediranib with the PARP inhibitor olaparib achieved varying results relative to resistance mechanism in patients with high-grade serous ovarian cancer experiencing resistance to PARP inhibitors. Performed by Amit M. Oza, MD, of the Princess Margaret Cancer Centre, Toronto, and colleagues, EVOLVE was the largest study at the time to focus on identifying gene-based resistance mechanisms to these inhibitors.
The study included 34 heavily pretreated patients with radiographic evidence of disease progression. They were placed in one of three cohorts: platinum sensitive after PARP inhibitor treatment (n = 11), platinum resistant after PARP inhibitor treatment (n = 10), or the exploratory cohort of disease progression on standard chemotherapy and after PARP inhibitor treatment (n = 13). All patients received 300 mg of olaparib twice daily plus 20 mg of cediranib once daily until disease progression or severe toxicity occurred.
Objective response rates were low among all groups, at 0 (0%) for the platinum-sensitive, 2 (20%) for the platinum-resistant, and 1 (8%) for the exploratory cohorts. At 16 weeks, the platinum-sensitive group had the highest progression-free survival rate at 55%, followed by 50% in the platinum-resistant group and 39% in the exploratory group. Overall, the most frequently occurring grade 3 toxicities were diarrhea (12%) and anemia (9%).
Acquired genomic alterations noted at the time of disease progression while on PARP inhibitor treatment included reversion mutations in BRCA1, BRCA2, or RAD51B (19%); CCNE1 amplification (16%); ABCB1 upregulation (15%); and SLFN11 downregulation (7%). Poor outcomes were associated with reversion mutations in homologous recombination genes and/or ABCB1 upregulation.
Disclosure: For full disclosures of the study authors, visit clincancerres.aacrjournals.org.