Targeted Chemotherapy for Ovarian Cancer with Homologous Recombination

Deficiency of late relapse

Randomized clinical trial comparing liposomal doxorubicin plus carboplatin vs. paclitaxel plus carboplatin for recurrent, platinum-sensitive epithelial ovarian cancer with dysfunctional homologous

recombination pathway

Ting-Chang Chang, MD, MPHProfessor and Chairman, Chang Gung Memorial Hospitals, North TaiwanPresident, Taiwan Precision Medicine Society

Sensitivity and improved survival are hallmarks of BRCA-mutated and BRCA-ness EOC

• Attributed to the homologous recombination deficiency in the absence of BRCA1/BRCA2/RAD51 function• Impaired ability to repair DNA double strain breaks

• Increased sensitivity to • Cisplatin/carboplatin

• doxorubicin

• trabectedin

• mitomycin C

• etoposide

• topotecan

• irinotecan

CALYPSOROC relapsing > 6 months after first- or second-line therapyPegylated liposomal doxorubicin (30 mg/m2) and carboplatin (AUC 5) at 4-week intervals vs. paclitaxel (175 mg/m2) and carboplatin (AUC 5) at 3-week intervals

J Clin Oncol 28:3323-3329.Br J Cancer. 2012 Aug 7; 107(4): 588–591.

Eric Pujade-Lauraine et al. JCO 2010;28:3323-3329 British Journal of Cancer (2012) 107, 588–591

CALYPSO

MITO-2Chemotherapy-naïve, IC - IV ovarian cancer randomly assigned to carboplatin AUC 5 + paclitaxel 175 mg/m2 or to carboplatin AUC 5 + PLD 30 mg/m2, every 3 weeks for 6 cycles.

J Clin Oncol 28:3323-3329.Br J Cancer. 2012 Aug 7; 107(4): 588–591.

Sandro Pignata et al. JCO 2011;29:3628-3635

©2011 by American Society of Clinical Oncology

Study regimens and compliance in CALYPSO and MITO-2Regimen Compliance

MITO-2PLD 30 mg/m2 + Carbo AUC 5, every 3 wks

81% completed 6 cycles vs. 86% of control

34.5% of cycles delayed vs. 11.5% in control

CALYPSOPLD 30 mg/m2 + Carbo, AUC 5 every 4 wks 85% completed 6 cycles vs.

77% of control

21 wks of treatment duration vs. 16 wks in control

Control (both)Pacliaxel 175mg/m2 + Carbo AUC 5, every 3 wks

Hypothetical Distributions of BRCA mutation or BRCAnessin primary and in platinum-sensitive recurrent Epithelial Ovarian Cancer

Primary Platinum Sensitive Recurrent

Clinical trial proposal

• A Randomized, Open-label, Multicenter, Phase III Study to Compare the Efficacy of Liposomal Doxorubicin plus Carboplatin versus Paclitaxel plus Carboplatin in Patients with BRCA-mutated Epithelial Ovarian Cancer of late relapse

• A Randomized, Open-label, Multicenter Study to Compare the Efficacy of Liposomal Doxorubicin plus Carboplatin versus Paclitaxel plus Carboplatin in Patients with previously untreated BRCA-mutated Epithelial Ovarian Cancer

platinum-sensitive recurrent epithelial ovarian cancer

screening

BRCAm/BRCAness (-)/mis-match repair deficiency

Chemo-free period, 6-12 m or >12 m

stratification

Standard C/T Study C/T

Gemline BRCA1/2 mutated/Somatic BRCA1/2 mutated/BRCAness

Chemo-free duration, 6-12 m or >12 .

stratification

Standard C/T Study C/T

Testing for BRCAm/BRCAness

triage

BRCAm, pathogenic BRCA1/2 mutationR, randomizeStandard C/T, choose either paclitaxel 175 mg/m2 + carboplatin AUC5, every 3 wks x 6 or dose-dense paclitaxel 80 mg/m2/D 1,8,15 + carboplatin AUC5, every 3 wks x 6Study C/T, liposomal doxorubicin 30 mg/m2 + carboplatin AUC5 every 4 wks x 6

R R

• Comments