Reference Detail

Ref Type

Journal Article

PMID

(32444417)

Authors

Lheureux S, Oaknin A, Garg S, Bruce JP, Madariaga A, Dhani NC, Bowering V, White J, Accardi S, Tan Q, Braunstein M, Karakasis K, Cirlan I, Pedersen S, Li T, Fariñas-Madrid L, Lee YC, Liu ZA, Pugh TJ, Oza AM

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research			2020 May 22	4206-4215	Clin Cancer Res

URL

Abstract Text

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.The proof-of-concept EVOLVE study (NCT02681237) 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-naïve) and baseline biopsy (post-PARPi) samples were mandatory. Genomic mechanisms of resistance were assessed by whole-exome and RNA sequencing.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.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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Cediranib	Cediranib	14	5

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Cediranib		AZD-2171\|Recentin\|AZD2171\|AZD 2171	KIT Inhibitor 57 VEGFR1 Inhibitor 6 VEGFR2 Inhibitor 37 VEGFR3 Inhibitor 6	Cediranib (AZD-2171) is an ATP-competitive inhibitor of all three vascular endothelial growth factor receptors (FLT1, KDR, and FLT4) and KIT, thereby blocking VEGF-signaling, angiogenesis, and tumor cell growth (PMID: 15899831, PMID: 24714778, PMID: 32444417).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RAD51B wild-type	ovary serous adenocarcinoma	predicted - sensitive	Cediranib + Olaparib	Clinical Study - Cohort	Actionable	In a Phase II trial, Cediranib (AZD-2171) and Lynparza (olaparib) treatment was well tolerated, and resulted in an objective response rate (ORR) of 9% (all partial), a 16-week progression-free survival (PFS) of 47%, and a disease control rate (DCR) of 68% in high-grade serous ovarian cancer patients (n=34), and a median PFS of 6.4 months and 1.9 months in patients harboring wild-type (n=9) and reversion mutations (n=5) in either BRCA1, BRCA2, or RAD51B, respectively (PMID: 32444417; NCT02681237).	32444417
RAD51B mutant	ovary serous adenocarcinoma	predicted - sensitive	Cediranib + Olaparib	Clinical Study - Cohort	Actionable	In a Phase II trial, Cediranib (AZD-2171) and Lynparza (olaparib) treatment was well tolerated, and resulted in an objective response (OR) of 9% (all partial), a 16-week progression-free survival (PFS) of 47%, and a disease control rate (DCR) of 68% in heavily pretreated high-grade serous ovarian cancer patients (n=34), and a median PFS of 4.8 months in patients (n=14) harboring mutations in either BRCA1, BRCA2, or RAD51B (PMID: 32444417; NCT02681237).	32444417