LBA42 - Olaparib vs placebo as maintenance therapy after platinum-based chemotherapy in advanced/metastatic endometrial cancer patients: The GINECO randomized phase IIb UTOLA trial

Background

The TGCA data suggest opportunities to target DNA repair in patients (pts) with endometrial cancer (EC). UTOLA assessed the efficacy of Parp-inhibitor maintenance for advanced/M+ EC pts who achieved disease control after 1st line platinum CT and to analyse efficacy in some molecular subgroups.

Methods

UTOLA is a randomized, double-blind, placebo controlled, phase IIb trial. Adjuvant CT ≥12 mos before inclusion was allowed. Pts were randomized (2:1) to olaparib maintenance arm (ola, 300 mg po BID) or placebo arm (pl) until progression or intolerance with stratification on P53, MMR status, and the response to the previous CT. Molecular profile was assessed by IHC and NGS. Primary endpoint was PFS in ITT. Main secondary endpoints were PFS according to P53 status, CT response, OS, safety. A pre-specified PFS analysis was performed according to HRD status defined by the number of large genomic events. One sided unstratified analyses are presented.

Results

147 pts were randomized (98 to Ola, 49 to pl). 82% of the pts received at least 6 cycles of CT with 46 CR, 64 PR, 34 stable and 3 NED; tumor classification was 53% P53_mut, 35% NSMP, 12% MMRd, and 1 tumor POLE_mut. In total, 52% (73) were HRD positive, 79% in P53_mut & 23% in P53_WT. Median PFS in the ITT population was 5.6 mos (90%CI 3.8-7.4) and 4.0 (3.6-7.4) in ola and pl arms respectively (HR:0.94, p=0.29). Median PFS in P53_mut were 5.6 mos (3.6-8.8) vs 3.6 ms (1.8-4.9) in ola and pl arms (HR:0.75, p=0.12) whereas 6.1 mos (3.6-11) vs 7.7 mos (2.9-14.5) (HR=1.13, p=0.3) respectively in the P53_WT. In the HRD tumors (n=73), median PFS was statistically higher with ola: 5.4 mos (90%CI 3.6-9.6) vs 3.6 mos (1.8-4.9) with pl (HR:0.59, p=0.02) regardless of P53 status. For the 46 pts with CR to previous CT, median PFS in ola arm reached 8.8 mos versus 3.8 mos. No difference for OS was observed in all subgroups. Safety profile was similar and acceptable as seen in other cancers (36% vs 10% of G3/4 toxicities without myelodysplasia with ola).

Conclusions

UTOLA suggests maintenance ola could prolong PFS in HRD-positive advanced/M+ EC. These data should be confirmed and warrants further PARP inhibitor studies in this population.

Clinical trial identification

EudraCT 017-002623-13.

Editorial acknowledgement

Legal entity responsible for the study

ARCAGY-GINECO.

Funding

AstraZeneca.

Disclosure

F. Joly Lobbedez: Financial Interests, Personal, Advisory Board: GSK, AstraZeneca, MSD, Janssen, Ipsen, BMS, Bayer, Eisai; Financial Interests, Personal, Invited Speaker: GSK, AstraZeneca, MSD, Janssen, Ipsen, Amgen, Astellas; Financial Interests, Institutional, Coordinating PI: GSK, AstraZeneca; Financial Interests, Institutional, Research Grant: BMS; Other, travel: MSD, GSK. A. Leary: Financial Interests, Personal, Advisory Board: Zentalis; Financial Interests, Personal, Invited Speaker, Educational: GSK, Medscape; Financial Interests, Personal, Writing Engagement, Educational: Onko+; Financial Interests, Institutional, Other, Steering committee: MSD; Financial Interests, Institutional, Advisory Board: GSK, AstraZeneca, Clovis, Ability Pharma, MSD, Merck Serono, Apmonia, Blueprint; Financial Interests, Institutional, Invited Speaker, Educational: Kephren publishing; Financial Interests, Institutional, Other, Consultancy: Orion; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Clovis; Financial Interests, Personal, Other, Consultancy: GLG; Financial Interests, Institutional, Research Grant, PI translational research: ARCAGY-GINECO, Sanofi, AstraZeneca; Financial Interests, Institutional, Funding, CI clinical trial: AstraZeneca; Financial Interests, Institutional, Research Grant, Int CI clinical trial: OSE immuno; Financial Interests, Institutional, Funding, PI clinical trial: Agenus, BMS, Iovance, GSK; Financial Interests, Institutional, Funding, PI 5 clinical trials: Roche; Financial Interests, Institutional, Funding, PI 2 clinical trials: AstraZeneca; Financial Interests, Institutional, Funding, PI 3 clinical trials and steering committee: MSD; Non-Financial Interests, Institutional, Other, Academic research project: Owkin, LXRepair; Non-Financial Interests, Personal, Proprietary Information, IDMC member: Clovis; Non-Financial Interests, Personal, Proprietary Information, IDMC chair: Pfizer; Non-Financial Interests, Member: GCIG. I.L. Ray-Coquard: Financial Interests, Personal, Advisory Board: Roche, GSK, AstraZeneca, Mersana, Deciphera, Amgen, Oxnea, Merck Sereno, Agenus, Novartis, Macrogenics, Clovis, EQRX, adaptimmun, Esai, SUTRO, BMS, Adaptimmune, Daiichi-Santyo; Financial Interests, Institutional, Other, COLIBRI translational research: BMS; Financial Interests, Institutional, Advisory Board, translational research NEOPREMBROV trial: MSD; Non-Financial Interests, Principal Investigator: PAOLA1; Non-Financial Interests, Other, President: GINECO. B. Asselain: Financial Interests, Advisory Board: DIALOG, Pierre Fabre; Financial Interests, Advisory Role: AstraZeneca, Daiichi Sankyo, Gilead; Financial Interests, Other, Training in Biostatistics: Servier, Roche. M.J. Rodrigues: Financial Interests, Personal, Invited Speaker: Immunocore; Financial Interests, Personal, Advisory Board: GSK, AstraZeneca; Financial Interests, Institutional, Coordinating PI: Johnson & Johnson; Non-Financial Interests, Institutional, Product Samples: MSD. L. Gladieff: Financial Interests, Personal, Other, Congress funding: VIATRIS, Roche; Financial Interests, Institutional, Invited Speaker: MSD, Clovis, GSK, Eisai; Financial Interests, Institutional, Advisory Board: CLOVIS, GSK; Financial Interests, Personal, Invited Speaker: AstraZeneca. F. Bazan: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Novartis, Eisai, Menarini; Financial Interests, Personal, Invited Speaker: Astra-Zeneca. C. Lebreton: Financial Interests, Personal, Advisory Board: GSK, GSK, MSD, Eisai, CLOVIS Oncology. L. Bengrine Lefevre: Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Invited Speaker: Servier, Eisai; Non-Financial Interests, Personal, Other: SOFOG, DIALOG. K. Leroy: Financial Interests, Personal, Other, scientific collaboration, speaker fees: Roche; Financial Interests, Personal, Invited Speaker: AstraZeneca, Janssen, Amgen, MSD, GSK; Non-Financial Interests, Principal Investigator, REALM study: Roche. R. Leman: Financial Interests, Institutional, Speaker, Consultant, Advisor, JEBP2023 - 2022-DIAG-0119: AstraZeneca; Financial Interests, Institutional, Speaker, Consultant, Advisor, AR_Staff_CFB-Biopathologie_23052023: AstraZeneca. P. Fournel: Financial Interests, Personal, Advisory Board: BMS, Sanofi, Janssen; Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Amgen; Financial Interests, Personal, Other, Congress invitation: Takeda; Financial Interests, Institutional, Local PI: BMS, IPSEN. F. Selle: Financial Interests, Personal, Other: AstraZeneca, GSK Tesaro, MSD, Sandoz (Novartis), Clovis Oncology; Financial Interests, Institutional, Other: Roche, GSK-Tesaro, AstraZeneca, Immunogen, Incyte, Agenus. J. Frenel: Financial Interests, Personal, Advisory Board: Pfizer, Novocure, Pierre Fabre, Eisai, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: GSK, Amgen; Financial Interests, Institutional, Advisory Board: Exactscience, Lilly, Daiichi Sankyo, AstraZeneca, Clovis Oncology; Financial Interests, Institutional, Invited Speaker: Novartis, MSD; Financial Interests, Coordinating PI: AstraZeneca, Seagen; Financial Interests, Local PI: MSD, Daiichi Sankyo; Non-Financial Interests, Principal Investigator: Novartis, Lilly, AstraZeneca, Pfizer, Daiichi Sankyo, MSD. Y. Fernandez: Financial Interests, Personal, Advisory Board: TESARO; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Local PI: GSK, AstraZeneca, Pfizer; Non-Financial Interests, Personal, Member: ASCO, ESMO, ESGO. C. Foa: Financial Interests, Personal, Other, speaker / participation in a speaker’s bureau: Roche, MSD, AstraZeneca. B. You: Financial Interests, Personal, Advisory Role: MSD, Astra-Zeneca, GSK-Tesaro, Bayer, Roche-Genentech, ECS Progastrine, Novartis, LEK, Amgen, Clovis Oncology, Merck Serono, BMS, Seagen, Myriad, Menarini, Gilead, Eisai. J. Alexandre: Financial Interests, Personal, Advisory Board: Eisai, MSD, GSK, Janssen, Pfizer; Financial Interests, Personal, Invited Speaker: Eisai, MSD, AstraZeneca, GSK, Novartis; Financial Interests, Institutional, Research Grant: Janssen, GSK, MSD; Financial Interests, Institutional, Local PI: MSD, Eisai, Agenus, GSK, Immunogen, Incyte. All other authors have declared no conflicts of interest.