LBA33 - Maintenance olaparib rechallenge in patients (pts) with ovarian carcinoma (OC) previously treated with a PARP inhibitor (PARPi): Phase IIIb OReO/ENGOT Ov-38 trial

Background

OReO/ENGOT Ov-38 (NCT03106987), a randomized, double-blind trial, is the first Phase III study to evaluate PARPi maintenance rechallenge.

Methods

Pts had non-mucinous platinum-sensitive relapsed (PSR) OC, one prior line of PARPi maintenance and were in response to their most recent platinum-based chemotherapy (PBC). Pts enrolled in BRCA1/2 mutated (BRCAm) (≥18 months [m] first-line [1L] or ≥12 m 2L+ prior PARPi exposure [PPE]) and non-BRCAm (≥12 m 1L or 6 m 2L+ PPE) cohorts were randomized (2:1; stratified by prior bevacizumab [yes vs no] and prior lines of PBC [≤3 vs ≥4]) to olaparib (O) tablets (300 mg bid [or 250 if 300 not previously tolerated]) or placebo (P) until progression. Primary endpoint was investigator-assessed progression-free survival (PFS; RECIST v1.1).

Results

112 pts were randomized in the BRCAm cohort (O: n=74; P: n=38); 108 in the non-BRCAm cohort (O: n=72; P: n=36). Pts were heavily pre-treated with 93% (BRCAm) and 86% (non-BRCAm) receiving ≥3 prior lines of any chemotherapy (see the table for other baseline characteristics). In the BRCAm cohort median PFS was 4.3 (O) vs 2.8 (P) m (hazard ratio [HR] 0.57; 95% CI 0.37–0.87; P=0.022); PFS rates (Kaplan–Meier method) were 35% vs 13% at 6 m and 19% vs 0% at 12 m. In the non-BRCAm cohort median PFS was 5.3 (O) vs 2.8 (P) m (HR 0.43; 95% CI 0.26–0.71; P=0.002); PFS rates were 30% vs 7% at 6 m and 14% vs 0% at 12 m. Subgroup analyses by HRD status in non-BRCAm pts will be presented. Grade ≥3 adverse events (AEs) occurred in 15% of O vs 5% of P BRCAm pts and 21% vs 8% of non-BRCAm pts. 3% BRCAm pts and 1% non-BRCAm pts discontinued O because of an AE vs no P pts. Table: LBA33

*Previously documented gBRCAm or sBRCAm by local testing. ^†gBRCAm negative by local testing; may include pts with undetected sBRCAm. ^‡GIS ≥42 and/or a qualifying tBRCAm based on retrospective tumour testing (Myriad myChoice CDx); ^§GIS <42 and no qualifying tBRCAm. BRCAm, BRCA1 and/or BRCA2 mutation; g, germline; GIS, genomic instability score; HRD, homologous recombination deficiency; s, somatic; t, tumour

Conclusions

The OReO/ENGOT Ov-38 trial is the first to provide data on PARPi rechallenge in PSR OC pts. The trial met its primary PFS endpoint. Maintenance O provided a significant improvement in PFS vs P, irrespective of BRCAm status. A proportion of pts derived clinically relevant long-term benefit. Safety was consistent with the known profile of O.

Clinical trial identification

NCT03106987.

Editorial acknowledgement

Medical writing assistance was provided by Elin Pyke, MChem, of Cence, funded by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

AstraZeneca.

Funding

This study was funded by AstraZeneca and is part of an alliance between AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

E. Pujade-Lauraine: Financial Interests, Personal, Invited Speaker: AstraZeneca, Tesaro, and Roche; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Tesaro, and Roche; Financial Interests, Personal, Other, Travel: AstraZeneca, Tesaro, and Roche; Financial Interests, Personal, Invited Speaker: Clovis Oncology, Incyte, and Pfizer; Financial Interests, Personal, Full or part-time Employment: ARCAGY Research. F. Selle: Financial Interests, Personal, Invited Speaker: AstraZeneca, GSK-Tesaro, MSD, Sandoz (Novartis), Clovis Oncology; Financial Interests, Institutional, Research Grant: Roche, GSK-Tesaro, AstraZeneca, Immunogen, MSD, Incyte, Agenus. G. Scambia: Financial Interests, Personal, Speaker’s Bureau: Clovis Oncology Italy Srl and MSD Italia Srl. B. Asselain: Financial Interests, Personal, Other, Honoraria: BMS, AstraZeneca, Roche, Daiichi, Servier, and Pierre Fabre. F. Marmé: Financial Interests, Personal, Other, Honoraria: AstraZeneca, GSK/Tesaro, Clovis, MSD, Novartis, Pfizer, Lilly, Roche, Gilead/Immunomedics, Eisai, Celgene, GenicHealth and Myriad Genetics; Financial Interests, Personal, Advisory Board, Consulting: AstraZeneca, GSK/Tesaro, Clovis, MSD, Novartis, Pfizer, Lilly, Roche, Gilead/Immunomedics, Amgen, Eisai, Celgene, PharmaMar, Janssen-Cilag, GenicHealth, Myriad Genetics and Seagen; Financial Interests, Personal, Research Grant: AstraZeneca, GSK/Tesaro, Clovis, MSD, Novartis, Pfizer, Roche, Gilead/Immunomedics, PharmaMar, GBG and AGO Studiengruppe. K. Lindemann: Financial Interests, Personal, Advisory Role: AstraZeneca, GSK and Eisai; Financial Interests, Personal, Research Grant: GSK. N. Colombo: Financial Interests, Personal, Other, Honoraria: Roche/Genentech, AstraZeneca, Tesaro and PharmaMar; Financial Interests, Personal, Advisory Board, Consulting: Roche/Genentech, PharmaMar, AstraZeneca, Clovis Oncology, Pfizer, MSD Oncology, Takeda, Tesaro, and BioCadand GSK. R. Madry: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche and GSK; Financial Interests, Personal, Funding: AstraZeneca, Roche and GSK. R.M. Glasspool: Non-Financial Interests, Personal, Principal Investigator: AstraZeneca, Clovis, GSK/Tesaro, Immunogen, AbbVie, Pfizer, Lilly and Novartis; Financial Interests, Personal, Funding: Clovis, Boehringer Ingelheim and Lilly/Ignyta; Financial Interests, Institutional, Funding: GSK/Tesaro; Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Clovis, Tesaro, GSK, Immunogen and Sotio; Financial Interests, Institutional, Other, Consultancy fee: Novartis. A. Oaknin: Financial Interests, Personal, Other, Consultancy fees: Roche, AstraZeneca, MSD/Merck, PharmaMar, Clovis Oncology, Tesaro/GSK, Immunogen, Genmab, SUTRO and Deciphera. C. Zamagni: Financial Interests, Personal, Advisory Board: Roche, Eisai, Novartis, AstraZeneca, Pfizer, PharmaMar, Amgen, Tesaro, QuintilesIMS, Lilly, Celgene; Financial Interests, Personal, Other, Travel accommodation: Roche, Novartis, Pfizer, PharmaMar, Tesaro, PierreFabre, Istituto Gentili, Celgene; Financial Interests, Institutional, Research Grant: Roche, Novartis, AstraZeneca, Pfizer, SeattleGenetics, Tesaro, PierreFabre, Istituto Gentili, Takeda, TEVA, Medivation, AbbVie, Array BioPharma, Morphotek, Synthon,; Non-Financial Interests, Personal, Member: Europa Donna italy, Susan J Komen Emilia-Romagna, LOTO Onlus, Mamazone Sudtirol. F. Heitz: Financial Interests, Personal, Other, Travel grants: AstraZeneca, Tesaro and Roche; Financial Interests, Personal, Other, Honoraria: Clovis and PharmaMar; Financial Interests, Personal, Funding: AGO studygroup; Financial Interests, Personal, Advisory Board: AstraZeneca, GSK and Roche. L. Gladieff: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Clovis Oncology, GSK, PharmaMar, Roche, and Tesaro; Financial Interests, Institutional, Other, Honoraria: Clovis Oncology, GSK, and MSD; Financial Interests, Personal, Advisory Board: AstraZeneca, Clovis Oncology, GSK, and Tesaro; Financial Interests, Personal, Funding: PharmaMar, Roche, and Tesaro. C. Blakeley: Financial Interests, Personal, Full or part-time Employment, Former employee: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. B. Shaw: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. I.L. Ray-Coquard: Financial Interests, Personal, Other, Honoraria: AbbVie, Agenus, Advaxis, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche, GSK, MSD, Deciphera, Mersena, Merck Sereno, Novartis, Amgen, Tesaro and Clovis; Financial Interests, Institutional, Other, Honoraria: GSK, MSD, Roche and BMS; Financial Interests, Personal, Advisory Board: AbbVie, Agenus, Advaxis, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche/Genentech, GSK, MSD, Deciphera, Mersena, Merck Sereno, Novartis, Amgen, Tesaro and Clovis; Financial Interests, Personal, Research Grant: MSD, Roche and BMS; Financial Interests, Institutional, Research Grant: MSD, Roche, BMS, Novartis, AstraZeneca and Merck Sereno; Financial Interests, Personal, Other, Travel grant: Roche, AstraZeneca and GSK. A. Redondo: Financial Interests, Personal, Other, Honoraria: MSD, AstraZeneca, Roche, GSK, Clovis, PharmaMar, Lilly, and Amgen; Financial Interests, Personal, Advisory Board, Consultancy fees: MSD, AstraZeneca, Roche, GSK, Clovis, PharmaMar, Lilly, and Amgen; Financial Interests, Institutional, Research Grant: Eisai, PharmaMar, and Roche; Financial Interests, Personal, Other, Travel grant: AstraZeneca, Tesaro, PharmaMar, and Roch; Financial Interests, Personal, Speaker’s Bureau: MSD, AstraZeneca, Roche, GSK, Clovis, and PharmaMar. All other authors have declared no conflicts of interest.