EVOLVE: A Multicenter Open-Label Single-Arm Clinical and Translational Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer after PARP Inhibition Progression

Abstract

Purpose: PARP inhibitors (PARPi) are standard-of-care therapy for high-grade serous ovarian cancer (HGSOC). We investigated combining cediranib (antiangiogenic) with olaparib (PARPi) at emergence of PARPi resistance.Patients and Methods: The proof-of-concept EVOLVE study (NCT-02681237) assessed cediranib-olaparib combination therapy after progression on a PARPi. Women with HGSOC and radiographic evidence of disease progression were enrolled into one of three cohorts: platinum sensitive after PARPi; platinum resistant after PARPi; or progression on standard chemotherapy after progression on PARPi (exploratory cohort). Patients received olaparib tablets 300 mg twice daily with cediranib 20 mg once daily until progression or unacceptable toxicity. The coprimary endpoints were objective response rate (RECIST v1.1) and progression-free survival (PFS) at 16 weeks. Archival tissue (PARPi-na€ ve) and baseline biopsy (post-PARPi) samples were mandatory. Genomic mechanisms of resistance were assessed by whole-exome and RNA sequencing.Results: Among 34 heavily pretreated patients, objective responses were observed in 0 of 11 (0%) platinum-sensitive patients, 2 of 10 (20%) platinum-resistant patients, and 1 of 13 (8%) in the exploratory cohort. Sixteen-week PFS rates were 55%, 50%, and 39%, respectively. The most common grade 3 toxicities were diarrhea (12%) and anemia (9%). Acquired genomic alterations at PARPi progression were reversion mutations in BRCA1, BRCA2, or RAD51B (19%); CCNE1 amplification (16%); ABCB1 upregulation (15%); and SLFN11 downregulation (7%). Patients with reversion mutations in homologous recombination genes and/or ABCB1 upregulation had poor outcomes.Conclusions: This is currently the largest post-PARPi study identifying genomic mechanisms of resistance to PARPis. In this setting, the activity of cediranib-olaparib varied according to the PARPi resistance mechanism.

Rationale for combination PARP inhibitor and antiangiogenic treatment in advanced epithelial ovarian cancer: A review

“…ovarian cancer (Table 3) [48]. Most importantly, this study identified possible mechanisms of PARP inhibitor resistance, including mutation reversion in BRCA and other homologous repair genes, upregulation of BRCA1/2, CCNE1 amplification and retinoic acid-inducible gene I (RIG-I)-like receptor downregulation.…”

“…PARP inhibitors combined with antiangiogenic agents demonstrated efficacy based on objective response rates and PFS [10,[44][45][46][47][48]; however, combination therapy has not been shown to be superior to standard-ofcare chemotherapy options [45,46].…”

The role of patient-derived ovarian cancer organoids in the study of PARP inhibitors sensitivity and resistance: from genomic analysis to functional testing

“…Furthermore, PARPi could also be effectively combined with drugs that target specific features unrelated to the DDR function. The proof-of-concept EVOLVE study (NCT02681237) assessed cediranib-olaparib combination therapy after progression on a PARPi [99]. Interestingly, the activity of cediranib-olaparib varied according to the PARPi resistance mechanism, and patients with reversion mutations in homologous recombination genes and/or ABCB1 upregulation had poor outcomes.…”

Major clinical research advances in gynecologic cancer in 2020

“…The phase II EVOLVE trial investigated combining cediranib with olaparib for ovarian cancer after progression on a PARPi [ 29 ]. Women with high-grade serous ovarian cancer were enrolled into 1 of 3 cohorts: platinum sensitive after PARPi; platinum resistant after PARPi; or progression on standard CTx after progression on PARPi.…”