134P - Doxorubicin and olaparib (OLA) synergism in high-grade serous ovarian (HGOC) and triple-negative breast cancer (TNBC) cell lines with olaparib-resistance

Background

An important proportion of patients receiving PARPi will become resistant. Doxorubicin is one of the drugs used as standard of care in HGSOC becoming resistant to platinum. The ROLANDO trial showed an encouraging activiy in platinum-resistant HGSOC of the combinacion of OLA-Doxo. The aim of our study was to assess if doxorubicin and OLA are synergistic in both PARP-I sensibitve and PARPi- resistant models.

Methods

8 cell lines, 4 parental and 4 corresponding OLA resistant clonal lines were used. One triple-negative breast cancer (TNBC) line (MDA-MB-231) and 3 HGSOC OLA-sensitive cell lines (PEO1, Kuramochi and SKOV3) were acquired. We generated 4 OLA resistant cell lines (MDA-MB-231-R, Kuramochi-R, PEO1-R and SKOV3-R) by exposure to OLA. IC50 of OLA and doxorubicin and the combination of both (combo) were calculated in all 8 lines (sensitive and resistance). Synergism between both drugs was assessed with the Chou Talalay method for combination index (CI) at Fa50. BRCA status (mutation vs wild type (wt)) was assessed by NGS in every line.

Results

When compared with parental lines DOXO IC50 was statistically superior in resistant cell lines except in PEO1-R suggesting a potential cross-resistant between OLA and DOXO. DOXO + OLA were synergistic in both parental and OLA-resistant lines in MDA-MB-231, PEO1 and SKOV3, with Fa50 for resistant lines=0.41 and 0.38 and 0.67 respectively. However, in Kuramochi combo was not synergistic, with Fa 50=1.36. DNA damage assessed by H2AX was similar between combo and DOXO single agent in all parental and resistant lines. Table: 134P

Conclusions

Our in vitro models suggest that OLA-resistant cells have a cross-resistance to Doxo. However synergistic effect of OLA+DOXO is observed in most OLA-resistant cell lines except in kuramochi-R. Further analyses will confirm whether this combination might be a valuable strategy to overcome OLA-resistance.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

INCLIVA.

Funding

AstraZeneca.

Disclosure

J.A. Perez Fidalgo: Financial Interests, Personal, Invited Speaker: AstraZeneca, Clovis, GSK, PharmaMar, AstraZeneca, Artios Pharma; Financial Interests, Personal, Advisory Board: AstraZeneca, GSK, Clovis, PharmaMar, Roche, Abilify Pharma; Financial Interests, Personal, Full or part-time Employment, Associate Professor: University of Valencia; Financial Interests, Institutional, Research Grant: GSK, PharmaMar; Financial Interests, Institutional, Invited Speaker: Novartis, AstraZeneca; Financial Interests, Institutional, Funding: GSK; Non-Financial Interests, Personal, Project Lead, Coordinating PI Phase III trial in breast cancer: Novartis; Non-Financial Interests, Personal, Member, Member of the Early Drug Development working group: ENGOT; Non-Financial Interests, Personal, Leadership Role, Member of the Executive Committee and Head of the Scientific Committee: GEICO; Non-Financial Interests, Personal, Leadership Role, Member of the Executive Committee and co-coordinator of Uterine Sarcoma Group: GEIS; Non-Financial Interests, Personal, Leadership Role, Co-chair Phase 2 group: GCIG; Non-Financial Interests, Personal, Member: BIG; Non-Financial Interests, Personal, Member, Adolescent and Young Adults working group: SEOM.M. Mendiola: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, MSD; Financial Interests, Personal, Invited Speaker: GSK; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Personal, Research Grant: PharmaMar; Financial Interests, Personal, Other: Roche, Pfizer. A. Redondo Sanchez: Financial Interests, Personal, Invited Speaker: MSD, AstraZeneca, GSK, Clovis, PharmaMar; Financial Interests, Personal, Advisory Board: MSD, AstraZeneca, GSK, Clovis, PharmaMar; Financial Interests, Institutional, Invited Speaker: Roche, Eisai, PharmaMar. B. Pineda Merlo: Financial Interests, Institutional, Research Grant: AstraZeneca. All other authors have declared no conflicts of interest.